Archive

• mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex.
• The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined.
• Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.

Macrocycle Screening against the C-Terminal Region of CHD4 Uncovers Its Role as an Interaction Hub in the Formation of the Nucleosome Remodeling and Deacetylase Complex ↗

• Ammonium salts built on natural cinchona alkaloids were explored as local anesthetics; the bicyclic quincoridine skeleton beat acyclic and monocyclic analogues.
• Lead CLA-1-3 blocked the rat sciatic nerve for more than 50 hours and potently inhibited voltage-gated sodium channels.
• A second compound, CLA-3-5, gave a sensory-selective block lasting up to about 3 hours at 0.30–0.60% concentration.

Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades ↗

• Structure-guided hybridization produced an indazole-based LRRK2 series; the initial piperidine compounds were potent but barely distinguished wild-type from G2019S mutant kinase.
• Replacing the piperidine with an octahydrocyclopenta[c]pyrrole widened the selectivity window while keeping good potency; compound 34 represents the new chemotype.
• The authors pitch it as an alternative starting point for next-generation, Parkinson's-directed LRRK2 inhibitors.

Discovery of G2019S Mutant Selective LRRK2 Inhibitors Based on an Indazole Octahydrocyclopenta[c]pyrrole-Based Hybrid Chemotype ↗

• Replaces the earlier phosphopeptide-based STAT6 PROTAC with non-peptide degraders designed for oral dosing.
• WW-210 degraded STAT6 at very low concentrations with a wide selectivity window over other STAT family members.
• It showed measurable oral bioavailability and degraded STAT6 in blood and spleen; in an atopic dermatitis mouse model it eased skin lesions, lowered serum IgE and reduced mast cell infiltration.

Discovery of a Potent, Selective, and Orally Efficacious STAT6 PROTAC for the Treatment of Atopic Dermatitis ↗

• Approved KRAS G12C drugs mostly trap the inactive GDP state and face resistance; this series targets the active GTP-bound state instead.
• A keto-indolizine HTS hit with an aniline-derived acrylamide binds Cys12 in the switch-II pocket; crystallography shows the warhead engaging the γ-phosphate of a GTP analogue.
• Optimization gave compound 17, orally bioavailable in preclinical species, which prolongs disruption of KRAS–cRAF binding and ERK signalling and produced complete regression in a pancreatic cancer xenograft.

Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRAS G12C with Potent Antitumor Activity ↗

• Combines an electrophile-first covalent fragment screen with a ligand-first strategy to target lysines in the allosteric latch site of SHP2 phosphatase.
• Computational and experimental analyses support the binding mode, and the work yields what the authors call the first potent, cell-active allosteric covalent inhibitors at this site.
• It shows the latch site is covalently tractable, opening routes to new allosteric SHP2 chemotypes.

Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗

• A recent NeurIPS competition showed top ML models trained on DEL data failing to generalize to out-of-distribution chemical space; this study tests whether structural modeling can bridge the gap.
• It benchmarks ML, Glide docking, GALigandDock and Boltz-2 cofolding on three biologically diverse targets screened against DELs built in several synthesis formats.
• ML does well in-distribution; the paper's focus is how each approach holds up on new chemistry.

Assessing the Generalizability of Machine Learning and Physics-Based Methods with DNA-Encoded Libraries ↗

• The earlier hit BTP15 protects host cells from Mtb-induced death by blocking phagosomal escape through MprB inhibition, but had poor pharmacokinetics.
• New benzothiophene analogues were screened for MprB inhibition, microsomal stability, toxicity and ex vivo efficacy in THP-1 and MRC-5 cells.
• The aim is a virulence-blocking route that avoids killing the bacterium directly, which may reduce resistance pressure.

Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB ↗

• TFEB, a transcription factor long seen as undruggable, was approached starting from eltrombopag, which has weak TFEB inhibitory activity alongside its Tpo-R agonism.
• SAR optimisation gave DCL1191, which binds TFEB, disrupts TFEB–DNA binding and shows reduced Tpo-R and MITF activity; modelling and mutagenesis support the binding mode.
• It represses TFEB target genes, blocks autophagic flux and is orally bioavailable, with activity in autophagy-hyperactivated glioblastoma cells.

Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB) ↗

• Second-generation HDAC6 inhibitors were designed from X-ray structures of earlier compounds bound to the zebrafish HDAC6 catalytic domain.
• Co-crystal structures of two leads showed engagement of S531 in the L2 loop; cells showed raised acetylated tubulin without a clear histone acetylation change.
• One lead cut A549 viability in 2D and 3D culture through pro-autophagic signalling and also affected phase-separation behaviour.

Structure-Based Design of HDAC6 Inhibitors Targeting the L2 Pocket: Modulating Autophagy and Liquid−Liquid Phase Separation in Lung Cancer ↗

• PDIA3, an ER oxidoreductase involved in folding glycosylated viral envelope proteins, is an underexplored host target for antivirals.
• A new N-hydroxyindole-2-carboxamide class, exemplified by AV22, inhibits PDIA3 and shows broad activity against major human respiratory viruses.
• In coronavirus-infected cells AV22 raised release of non-infectious particles and reduced disulfide bond formation in spike.

Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses ↗

• A three-cycle, peptide-like DEL of 403,200 compounds was built, with a chemical space model of 4,774 commercial amino acids used to find under-represented building blocks.
• Affinity selections were run against three targets to compare library performance.
• Selection against carbonic anhydrase II recovered the known sulfonamide pharmacophore, supporting the computational design approach.

Design, Synthesis, and Comparative Selection Analysis of a Chemically Diverse Peptide-Like DNA-Encoded Library ↗

• Host-directed dual inhibition of PI4KIIIβ and HDACs had not previously been reported for hepatitis C, where resistance to direct-acting antivirals remains a concern.
• A series of thiazolamide-based dual inhibitors was designed, synthesised and evaluated.
• Lead compounds showed potent enzymatic inhibition of both targets together with anti-HCV activity.

Discovery of Thiazolamide-based PI4KIIIβ/HDAC Dual Inhibitors with Potent Activity against Hepatitis C Virus ↗

• SAR work identified D4, which binds STING directly and blocks its oligomerization and downstream TBK1/IRF3 signalling.
• In macrophages it restored phagocytosis, autophagic flux and mitochondrial function while dampening NLRP3-linked pyroptosis.
• D4 was orally exposed and well tolerated at high dose, and cut pancreatic injury and enzyme levels in a caerulein/LPS model; STING knockdown looked similar.

Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis ↗

• The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
• Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
• It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.

Discovery of a Novel Dual Inhibitor Targeting Tubulin and Histone Deacetylase 8 for Treatment of the Ovarian Cancer ↗

• A solid-phase route enabled systematic variation of VHL ligand, exit vector and linker in vorinostat-derived HDAC6 PROTACs.
• Longer, semi-rigid linkers gave the best degradation; the lead compounds degraded HDAC6 preferentially in MM.1S and MV4-11 cells.
• A matched non-degrading control with similar HDAC inhibition was clearly less antiproliferative, pointing to degradation itself as the driver.

Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation ↗

• Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
• The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
• Protection was also seen in zebrafish, extending PROTAC use beyond oncology.

Enhancing Natural Product Therapy with PROTACs: Targeted Degradation of TLR4 Confers Potent Endothelial Protection ↗

• SAR optimization of earlier virtual-screening hits, themselves derived from the antagonist NIBR189, gave full GPR183 agonists with complete G protein bias.
• The lead, TUG-2604, matches the endogenous oxysterol 7α,25-OHC in potency and efficacy without recruiting β-arrestin2.
• It failed to drive human dendritic cell migration on its own and blocked migration induced by the oxysterol.

Development of Potent G Protein Pathway-Biased GPR183 Agonists ↗

• Scaffold-hopping virtual screening produced a diaryl pyrimidine-guanidine series against the JmjC demethylase KDM6B, which is overexpressed in cervical cancer.
• The optimized lead matched GSK-J4 in enzyme potency but is non-competitive with 2-oxoglutarate, a different binding logic from most JmjC inhibitors.
• Despite pan-KDM activity in vitro, it selectively raised H3K27me3 in C33A cells and slowed xenograft growth.

Discovery of Diaryl Pyrimidine-Guanidine Derivatives as Jumonji C Domain-Containing Lysine Histone Demethylase (KDM) Inhibitors with In Vivo Anti-Cervical Cancer Activity ↗

• Dual ligands fuse the MOR partial agonist TRV734 with a D3R-antagonist trans-cyclopropylamine scaffold, aiming at safer opioid analgesics.
• (R)-LS02-14 and TRV734 gave robust antinociception but similar abuse-liability and respiratory-depression signals.
• (R)-LS01-64, with a much lower D3R/MOR ratio, gave modest analgesia but weaker reinforcing and conditioned-reward effects and minimal respiratory impact.

Further Development of Dual-Target Mu Opioid Receptor-Dopamine D3 Receptor (MOR-D3R) Ligands as Novel Therapeutics ↗

• SAR and property work on the 3-(biphenylethynyl)-1H-indazole scaffold behind CDD-2807 targeted its poor kinetic solubility.
• CDD-3094 kept nanomolar cellular potency while gaining solubility, lowering hERG liability and showing a clean broad kinase panel.
• A co-crystal structure guided changes against the main off-target CLK4, giving a strongly selective biochemical tool whose cellular potency dropped.

Design, Synthesis, and Pharmacological Profiling of Serine/Threonine Kinase 33 (STK33) Inhibitors for Nonhormonal Male Contraception ↗

• Donepezil-based derivatives were designed and made as dual inhibitors of human butyrylcholinesterase and fatty acid amide hydrolase.
• Lead G15 inhibited both enzymes in a balanced way, with sub-micromolar to low-micromolar activity.
• It showed measurable selectivity over the carboxylesterases CES1 and CES2, a common liability for serine-hydrolase inhibitors.

Design, Synthesis and Evaluation Donepezil-Based Dual BuChE/FAAH Inhibitors for Alzheimer's Disease Therapy ↗

• FlexENN is a message-passing graph neural network built on a local interface graph with geometry, flexibility descriptors and sequence per residue.
• Two models are trained independently: one for folded complexes and one for complexes with a disordered partner, using a newly built IDP dataset.
• Benchmarks include tubulin–tubulin interfaces in microtubules and microtubule–MAP complexes.

FlexENN: A Graph Neural Network for Binding Energy Prediction of Globular and Intrinsically Disordered Protein Complexes ↗

• Structure-guided hybridization of an indazole with an octahydrocyclopenta[c]pyrrole gave a new LRRK2 inhibitor chemotype for Parkinson's disease.
• Early piperidine-containing analogs were potent but barely distinguished wild-type from G2019S LRRK2.
• Swapping the piperidine for the fused bicyclic amine was the change introduced to widen that selectivity window.

Discovery of G2019S Mutant Selective LRRK2 Inhibitors Based on an Indazole Octahydrocyclopenta[c]pyrrole-Based Hybrid Chemotype ↗

• A Trojan-horse design hijacks bacterial iron uptake to move a β-lactam payload across the Gram-negative outer membrane.
• Ampicillin was conjugated to mono-catecholate, bis-catecholate and catecholate–hydroxamate siderophores and the series compared.
• The bis-catecholate conjugate is reported as the selective one, extending ampicillin's reach to multidrug-resistant P. aeruginosa.

A Selective Bis-Catecholate Siderophore-Ampicillin Conjugate Expands Activity against Multidrug-Resistant Pseudomonas aeruginosa ↗

• The oxidation-sensitive thioether in an IL-11-binding peptide was replaced with a lactam bridge, with linker length screened systematically.
• The optimized analog 4L6–16 bound IL-11 with good affinity and antagonized it more strongly than the starting peptide.
• It showed renoprotective effects in both cell and animal models of renal fibrosis.

Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment ↗

• Guided by earlier crystal structures, kinetic target-guided synthesis was used to assemble inhibitors of the P. aeruginosa virulence factor elastase LasB.
• Extensive SAR gave hydroxamic acid inhibitors with very high potency and good selectivity over a panel of human off-targets.
• The compounds protected lung epithelial cells from LasB damage, showed in vivo efficacy, and reached lung exposure above their biochemical potency.

Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB ↗

• The charged amino bisphosphonate inhibitor ARC39 of acid sphingomyelinase was masked to improve cell entry.
• Masked derivatives reached nanomolar activity in cells, about two orders of magnitude better than the parent.
• Cell uptake, stability and related properties were characterized in detail.

Masked Bisphosphonate Inhibitors of Acid Sphingomyelinase: Improved Cell Penetration and Potency ↗

• Only temozolomide and vorasidenib are approved brain-permeable, orally available drugs for brain cancers, so the team sought new brain-penetrant options.
• SAR work yielded a new class of highly brain-penetrant tubulin ligands; co-crystal structures confirm colchicine-site binding, with the tubulin βT7 and αT5 loops flipped relative to the colchicine-bound state.
• SAR showed high sensitivity to substitution with few indispensable moieties, leading to compound 40 as the clinical candidate.

Discovery and Optimization of a Novel Brain-Penetrant Colchicine-Binding Site Ligand for Treatment of Glioma ↗

• DNMT1 drives fibrogenesis through both catalytic and non-catalytic mechanisms, so the team built PROTAC degraders starting from DC-517 to hit both at once.
• Lead compound B7 mediates ubiquitin-proteasome degradation of DNMT1, lowers global DNA methylation and suppresses profibrotic responses in vitro.
• In vivo, B7 reduced DNMT1 levels and attenuated liver fibrosis, with less collagen deposition and better hepatic function.

Discovery of Potent, Selective DNMT1 PROTAC Degraders: Simultaneous Blockade of Catalytic and Non-Catalytic Functions for Liver Fibrosis Therapy ↗

• ENPP1 hydrolyzes cGAMP in the tumor microenvironment and so dampens STING-driven antitumor immunity.
• Inspired by the phosphate-based inhibitor STF-1084, the team made non-nucleotide inhibitors with a boronic acid zinc-binding group, leading to compound 36, which stays potent across pH.
• Compound 36 boosted cGAMP-mediated STING activation in vitro and gave tumor growth inhibition as monotherapy in a syngeneic CT26 model, with a synergistic effect alongside oxaliplatin and no observed toxicity.

Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy ↗

• FragDock builds molecules from synthetically accessible building blocks via known reactions and scores them by tethered docking that restrains a predefined core pose.
• FragDockRL adds reinforcement learning: rewards from rDock tethered docking followed by SMINA scoring drive a modified Deep Q-Network that guides stepwise molecular growth.
• The method was evaluated on three therapeutically important protein targets, including a receptor tyrosine kinase.

FragDockRL: A Reinforcement Learning Method for Fragment-Based Ligand Design via Building-Block Assembly and Tethered Docking ↗

• KTT-1 (compound 12) was identified as HDAC2-selective by evaluating both thermodynamics and kinetics of enzyme–inhibitor binding, rather than affinity alone.
• Crystallography of HDAC2 with the compound, plus quantum chemical calculations on model compounds, suggests its 2-furanyl group drives the selectivity.
• In cells it preferentially inhibited HDAC2 over the highly homologous HDAC1 and promoted neurite outgrowth; in stress-vulnerable mice it improved memory and depression-like behavior.

Discovery of an HDAC2-Selective Inhibitor via Enzyme−Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug ↗

• Pan-Hsp90 inhibitors stalled clinically because of their broad inhibition, so Hsp90β-selective indazolone compounds have been pursued, though earlier ones needed long optimization to become drug-like.
• This work modifies the northern indazolone fragment and the southwestern appendage at the same time, testing whether the best traits of each region can be combined.
• The resulting chimeric inhibitors retain Hsp90β affinity and selectivity while shifting key pharmacokinetic parameters.

Chimeric Hsp90β-Selective Inhibitors Confer Enhanced Affinity, Selectivity, and Drug-Like Properties ↗

• A bicyclopiperazine hit from a DNA-encoded library was optimized by structure-guided design into compound 1.5 (MAGLi 432), a reversible MAGL inhibitor.
• The compound combines high potency, selectivity over other serine hydrolases and CNS drug-like properties, with a favorable oral half-life in rats.
• It inhibited MAGL in human brain homogenate and worked in mouse neuroinflammation models; the campaign was steered by a translational "Five-Star Matrix" framework.

Translational Application of the Five-Star Matrix for the Structure-Guided Optimization of a Bicyclopiperazine DEL Hit into Bcpz 1.5: A Potent Monoacylglycerol Lipase Inhibitor with Functional Inhibition in Human Brain Homogenate and Efficacy in Neuroinflammatory Models ↗

• QPCT and Golgi-bound QPCTL convert N-terminal glutamines to pyroglutamate, affecting Aβ oligomerization, chemokine stability and CD47–SIRPα signaling.
• A virtual screen selecting under 0.1% of an in-house library, based on similarity to bioactive conformations of known inhibitors, delivered new chemotypes and sped up hit discovery.
• Structure-guided optimization of a quinazolidinone series gave the cellular tool compound BI-3614, with improved activity over earlier inhibitors.

Accelerated Hit Identification and Optimization of a Novel Class of Cellularly Active QPCT/L Inhibitors ↗

• Using 403 SARS-CoV-2 main protease structures from the open COVID Moonshot campaign, the authors asked how many new crystal structures are worth collecting.
• Similar reference ligands give the best pose prediction, and success plateaus at roughly five structures per Bemis-Murcko scaffold, exceeding 95% for the lead series.

How Many Crystal Structures Do You Need to Trust Your Docking Results? ↗

• Oral sGC stimulators can cause systemic hypotension and worsen ventilation-perfusion mismatch in PH-COPD, motivating a lung-restricted design.
• SAR and PK work identified high systemic clearance and low permeability as the key drivers of pulmonary selectivity.
• Compound 15 (frespaciguat, MK-5475) is a very potent stimulator with long target residence time and more than 200-fold unbound lung-to-plasma exposure after inhalation, with efficacy in a rat chronic hypoxia model.

Frespaciguat (MK-5475): A Novel Inhaled Soluble Guanylate Cyclase Stimulator for Pulmonary Hypertension Associated with COPD ↗

• Starting from a literature-derived PERK inhibitor of moderate potency but good kinase selectivity and PK, the team ran a lead optimization campaign steered by log D and lipophilic ligand efficiency.
• This produced APL-11056 (compound 49), a potent and selective PERK inhibitor with excellent in vivo pharmacokinetics.
• High permeability is linked to a fluorine alpha to the core benzamide, which appears to limit efflux-transporter recognition.

Discovery of a Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) Inhibitor Suitable for Clinical Progression ↗

• POLQ drives microhomology-mediated end joining, making it a synthetic-lethal target in homologous-recombination-deficient cancers.
• Optimizing a weak biochemical hit gave benzimidazole/purine inhibitors; compound 37 is potent, selective and orally active.
• In BRCA2-deficient DLD-1 cells it was antiproliferative and boosted olaparib, with no effect in HR-proficient cells; chronic oral dosing with olaparib regressed xenografts.

Discovery of a Novel Series of Benzimidazoles/Purines as Potent, Selective and Orally Active Inhibitors of the DNA Polymerase Activity of POLQ ↗

• Covalent sulfonium modification of the natural pneumocandin B0 scaffold gave derivatives active against Candida and able to reverse innate Cryptococcus neoformans resistance (MIC as low as 2 μg/mL).
• The modification raised fungal membrane permeability and caused depolarization while strengthening glucan synthase inhibition.
• Leads 3h and 5h showed low resistance potential, good safety and PK, and in vivo antifungal efficacy.

Sulfonium Modification of Echinocandins: An Effective Strategy to Combat Intrinsically Resistant Cryptococcus via Membrane Disruption and Enhanced Cell Wall Biosynthesis Inhibition ↗

• ATP-competitive inhibitors struggle to separate ULK1 from the near-identical ULK2, so the authors built cereblon-recruiting degraders instead.
• Structure-guided optimization gave MR-9036, which degrades ULK1 without touching ULK2 or IMiD neo-substrates, with ternary complex formation and proteasome dependence confirmed.
• After compound washout it kept autophagy suppressed longer than the clinical ULK1/2 inhibitor DCC-3116, with antitumor activity in KRAS G12C NSCLC models.

Discovery and Optimization of Isoform Selective ULK1 Degraders to Enhance Antitumor Activity in KRAS-Mutant Cancer ↗

• Comparative models of the structurally unresolved NS4B across all four dengue serotypes reveal a conserved transmembrane pocket that fits known resistance mutations.
• Docking of the JNJ-series inhibitors fed predictive field-based 3D-QSAR models, which were used to screen bioisosteres and in-house compounds.
• The top candidate, BNJ-495, was extremely potent against serotype 2 with a high selectivity index, and its conserved binding contacts suggest broad-spectrum activity.

Structure-Guided Design of a Subnanomolar Dengue Virus NS4B Inhibitor ↗

• Lanosterol inhibits protein aggregation but has poor physicochemical and PK properties, so the authors tuned the hydrophilic–lipophilic balance around the 3-hydroxyl and the aliphatic side chain.
• Systematic screening gave compound 10, with markedly better metabolic stability and drug-like properties.
• Oral dosing of 10 rescued memory deficits and reduced Aβ burden in an Alzheimer's mouse model.

Discovery of a BBB-Penetrant Lanosterol Derivative as an Aβ Aggregation Inhibitor for Alzheimer’s Disease ↗

• A library of chiral imidazoquinolines was made and profiled in HEK-Blue hTLR7 and hTLR8 reporter assays.
• The SAR identified a potent dual TLR7/8 agonist and, from the same family, a dual antagonist.
• Activity depended on stereochemistry, likely because the two enantiomers interact differently in the TLR7/8 binding pocket.

Investigation of Chiral Imidazoquinoline Based Heterocyclic Small Molecules on TLR7/8 Modulatory Activity ↗

• PKMYT1 restrains CDK1 at the G2/M checkpoint, and blocking it forces premature mitotic entry, DNA damage accumulation and cancer cell death.
• The patent overview covers the design, synthesis and therapeutic potential of a new carboxamide-based inhibitor series.
• The authors note potential to enhance ATR inhibitors, PARP inhibitors, chemotherapy and radiotherapy.

Novel Carboxamide-Based PKMYT1 Inhibitors for Replication Stress-Associated Cancers ↗

• HQY1480 is a PROTAC built on the macrocyclic fourth-generation EGFR inhibitor BI-4020, with the linker and E3 ligand optimized systematically.
• It degraded several clinically relevant EGFR mutants at low nanomolar concentrations, and proteomics showed no detectable off-target degradation.
• It outperformed BI-4020 in xenografts, including osimertinib-resistant models, and degraded EGFR in patient-derived xenografts.

Development of Potent and Selective EGFR-PROTACs Based on Macrocyclic Fourth-Generation EGFR Inhibitors ↗

• HIPK4 is a spermatid-specific kinase needed for sperm head shaping, making it a candidate non-hormonal contraceptive target.
• A cyanoquinoline series gave potent, HIPK4-selective inhibitors, selective within the HIPK family and across the kinome.
• Some compounds also altered HIPK4 proteostasis in spermatids, causing insoluble aggregates and recruiting the autophagy receptor TAX1BP1.

Small-Molecule Modulators of HIPK4 Activity and Proteostasis ↗

• Most OGG1 work has aimed at inhibitors; these mitochondria-enriched ORCAs instead reprogram the enzyme's catalysis.
• Biochemistry, mutagenesis and X-ray crystallography showed active-site binding that favors beta-elimination over glycosylase turnover.
• ORCAs protected mitochondrial function under oxidative stress, raised NAD levels in cortical neurons and were neuroprotective in a retina axotomy model.

Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress ↗

• A hydrogen-bond donor-to-acceptor conversion was used to lower the donor count of a 4-aminoquinazoline PKMYT1 series and improve drug-likeness.
• Lead 12f was a nanomolar enzyme inhibitor, potent in OVCAR-3 ovarian cells and synergistic with PARP inhibitors.
• With acceptable oral PK, it showed efficacy in an OVCAR-3 xenograft and was well tolerated.

Discovery of 4-Aminoquinazoline Derivatives as Potent PKMYT1 Inhibitors via Hydrogen Bond Donor-To-Acceptor Conversion for CCNE1-Amplified Cancers ↗

• The anti-Parkinsonian drug istradefylline showed modest NLRP3 inhibition, and optimizing it gave a thienopyrimidinone series.
• Lead L22 was roughly tenfold more potent than istradefylline, bound the NLRP3 NACHT domain directly and blocked inflammasome assembly.
• It was orally bioavailable, eased symptoms in a DSS colitis model and looked safe in acute and subacute toxicity studies.

Design, Synthesis, and Anti-Inflammatory Activity Evaluation of Novel thieno[2,3-d]Pyrimidin-4(3H)-One-Based NLRP3 Inflammasome Inhibitors ↗

• YTHDF1, YTHDF2 and YTHDF3 read m6A-modified mRNA in the cytosol, and this preprint reports a protein structure-based medicinal chemistry campaign against them.
• The aim is ligands that bind all three paralogs, rather than one reader at a time.
• Only the abstract opening was accessible, so potency and cellular data are not covered here.

Structure-Based Design of Potent Pan-YTHDF Ligands ↗

• A 67-compound SAR campaign on pyridazine-containing nicotinamides gave E6 as the most active FTO inhibitor, with binding confirmed by MST, CETSA and DARTS.
• E6 was active against MOLM-13 cells, raised global m6A, upregulated ASB2 and RARA and lowered c-Myc.
• It showed acceptable CYP safety and PK and inhibited MOLM-13 xenograft growth.

Discovery of Novel Pyridazine-Containing Nicotinamide Derivatives as Potent FTO Inhibitors for Acute Myeloid Leukemia ↗

• Starting from LLC0424, an NSD2 degrader that also engages GSPT1, a single-atom change gave two close analogues: 424-ND (NSD2-selective) and 424-GD (GSPT1-selective).
• 424-ND suppressed androgen receptor signaling in prostate cancer cells, while 424-GD triggered the integrated stress response.
• Biolayer interferometry showed distinct ternary-complex cooperativity for each target, and simulations suggested different low-energy conformations explain the bias.

Single-Atom Modification Enables Reversal of Degradation Selectivity between NSD2 and GSPT1 ↗

• Azido-functionalized VEGFR2 inhibitors EYE1090 and EYE1118 bind the receptor in a light-triggered way while staying potent in the dark.
• Green light that reaches the human retina, including in older eyes, boosted their anti-angiogenic activity in vitro.
• Given orally, both suppressed VEGF-induced retinal leakage in rats and shrank lesions in a mouse choroidal neovascularization model without acute liver toxicity.

Three Nitrogen Atoms Turn Old Kinase Inhibitors Into New Targetable Remedy ↗

• A viability-based phenotypic screen flagged GSPT1 as a vulnerability in glioblastoma cells, where resistance to temozolomide arises quickly.
• Optimizing an isoindolinone series for metabolic stability gave LG-NE-29, a molecular glue that drives CRBN-dependent ubiquitination and proteasomal degradation of GSPT1.
• It is reported to avoid the metabolic weaknesses of earlier scaffolds, and to be orally bioavailable with activity in glioblastoma xenograft models.

Discovery of LG-NE-29: An Orally Bioavailable GSPT1 Molecular Glue Degrader Effective in Glioblastoma Xenograft Models ↗

• Mutant KRAS variants are structurally diverse and lack druggable pockets, which has limited small-molecule inhibitors.
• The authors assemble a degrader on a six-helix-bundle DNA origami scaffold that targets the mRNA rather than the protein.
• One module pairs an engineered barnase variant with a programmable recognition strand, cutting RNA directly without relying on endogenous cellular machinery; a second module is designed for cell penetration.

An Integrated DNA Origami-Based RNA Degrader for Targeted Degradation of Oncogenic Mutant KRAS mRNA ↗

• PAPP-A is a secreted metalloproteinase that cleaves IGF-binding proteins to control local IGF signaling, offering an alternative to IGF-1R targeting.
• Inhibitors were built on an IGFBP-5-derived anchor sequence, with the scissile bond replaced by phosphinate or phosphonate groups, giving potent and selective compounds.
• Cryo-EM showed how they bind the active site, and they blocked IGFBP-4 and IGFBP-5 cleavage.
• They suppressed IGF-1 signaling in A549 cells, comparably to stanniocalcin-1, and inhibited Papp-aa-dependent signaling in vivo.

Synthetic inhibitors of pregnancy-associated plasma protein-A regulate IGF-1 signaling in vitro and in vivo ↗

• ACER2 hydrolyses ceramides to sphingosine and fatty acids, and no pharmacological tool for it existed.
• KPB82, a dodecane sulfonamide carrying a ceramide-like hydroxyphenylpropyl group, inhibited ACER2 potently, with minimal activity on acid and neutral ceramidases and none on ACER1 or ACER3.
• Kinetics were competitive, and docking into an AlphaFold3 model placed it in the substrate pocket near the Zn2+-binding histidines.
• The title reports protection of tumor and primary cells from doxorubicin cytotoxicity.

KPB82 potently and selectively inhibits ACER2 and protects tumor and primary cells from doxorubicin-induced cytotoxicity ↗

• Michael acceptors are masked with a hydroxylamine; a bioorthogonal reaction with a cyclooctyne triggers Cope elimination, regenerating the electrophile under mild conditions.
• The approach covers several warhead types, including unsaturated carbonyl, cyano, sulfonyl, phosphonate and maleimide, with tunable activation rates.
• Functionalized cyclooctynes can release an imaging or functional payload at the same time, giving a signal that reports activation.
• Applied to covalent inhibitors, it gave controlled activation in cells.

A Click-Triggered Bioorthogonal Strategy for Dual Activation of Covalent Warheads and Reporter Payloads ↗

• Knowledge-based potentials are interpretable scoring functions, but most treat space around protein atoms as isotropic.
• DESPOT is an all-atom anisotropic potential that assigns atoms to isotropic, axially symmetric or fully anisotropic classes by hybridization and bonding.
• It uses a positionally averaged reference state and a 'void' ligand atom type so regions preferentially left empty can be represented.
• The authors position it as a direction-aware successor to existing knowledge-based scoring.

DESPOT: Direction-Enhanced Scoring POTentials for Scoring of Protein–Ligand Interactions ↗

• CD73 is the rate-limiting enzyme of the adenosine pathway and a tumor-immunosuppression target.
• An aryl alkyl ether series was designed; LB10 emerged as the most promising, potent in both biochemical and cell assays.
• Enzyme kinetics and co-crystallography confirmed competitive inhibition.
• LB10 had low cytotoxicity and good pharmacokinetics, and oral dosing curbed tumor growth in a syngeneic Lewis lung carcinoma model, alone or in combination.

Discovery of LB10, a Potent and Orally Bioavailable Inhibitor of Ecto-5′-Nucleotidase as a Single Agent or in Combination for the Treatment of Lung Cancer ↗

• Linker optimization in targeted protein degradation is still largely empirical.
• The preprint asks whether current computational methods can rank close linker analogues before synthesis, the finest chemical differences yet tested.
• It uses a matched-pose design on VHL-recruiting SHP2 degraders to isolate the effect of the linker.
• This is a preprint, not yet peer reviewed; the snippet-level abstract available limits detail on the outcome.

Scoring close linker analogues in PROTAC ternary complexes: A matched-pose study of VHL-recruiting SHP2 degraders ↗

• GPCR–TfR1 targeting chimeras (GTACs) are bispecific antibodies that pair a receptor binder with a transferrin-receptor binder.
• They drive endocytosis and lysosomal degradation of the GPCR, rather than blocking the orthosteric site.
• Reported for BILF1, RXFP1 and CCR6, covering viral, cancer and immune targets that are hard to drug.
• Signalling, including constitutive activity, was fully shut down, with markedly greater potency than conventional antibody antagonists.

GPCR antagonism via rewiring of receptor trafficking and degradation ↗

• Review of soft drug design: molecules built to be rapidly and predictably inactivated by metabolism after acting.
• Typically close analogues of a validated lead, with a hydrolytically labile group (often an ester) as the deliberate soft spot.
• Highlights topical soft drugs in development, where local skin activity and low systemic exposure are the goal.
• Also covers practical considerations, open challenges and future directions.

Soft drugs: design principles and topical applications ↗

• OGT/OGA inhibition affects thousands of substrates, so protein-specific O-GlcNAc functions are hard to assign; OGTACs address this by recruiting OGT to a chosen protein.
• Each OGTAC joins an OGT-engaging element, a linker and a target-recognition motif, and can partly bypass TPR-domain substrate recognition.
• Productive O-GlcNAc writing needs proper ternary-complex formation and noninhibitory OGT binding, while the target-recognition motif sets targetable scope and selectivity.
• Local installation is linked to changes in protein turnover, signaling and transcription.

Chemically Induced Proximity for Targeted Protein O-GlcNAcylation ↗

• Anti-CD3 Fabs (OKT3, UCHT1) are sterically masked by leucine-zipper coiled-coil domains fused through protease-cleavable linkers, and paired with PSMA- or HER2-targeting nanobodies.
• Masking strongly lowered CD3 binding, and protease cleavage restored most of it, both on recombinant CD3 and on T cell-displayed CD3.
• Masked constructs did not activate Jurkat cells, whereas unmasked ones did.
• MMP2-cleavable versions drove MMP2-dependent killing of PSMA+ and HER2+ cancer cells in PBMC co-cultures, aiming to limit on-target off-tumor toxicity.

Proteolytic Activation of T Cell Engagers And Bispecific Proteins Using Modular Coiled-Coil Peptides ↗

• JK-4b, a potent NNRTI active against wild-type and clinical HIV-1 variants, was shelved because of high cytotoxicity; the authors used it as a lead for new analogues.
• Structure-guided designs addressing the NNRTI entrance channel gave a series with lower cytotoxicity and improved selectivity.
• Lead compound 9n retained strong potency against common resistance mutants, including double mutants, at levels comparable to etravirine.
• 9n also showed minimal cytochrome P450 inhibition and good human liver microsome stability, supporting further development.

Targeting the HIV-1 NNRTI Entrance Channel: Structure-Guided Optimization for Enhanced Safety and Selectivity ↗

• Reviews nonpeptidic GLP-1 receptor agonists that reached the clinic, including danuglipron, lotiglipron, DA-302168S and orforglipron, as case studies of how each solved the oral-delivery problem.
• Notes the design challenges these first-generation molecules still leave open.
• Proposes next-generation approaches: peptidomimetic design, multi-target agonists, and exploiting orthosteric-allosteric cooperativity.
• Covers practical aspects such as screening cascades, preclinical species choice, formulation and early safety assessment, with relevance to other difficult GPCRs.

Oral Small-Molecule GLP-1 Receptor Agonists: Lessons from Clinical Candidates and a Blueprint for Next-Generation Design ↗

• Scope defines a chemical space between fragments and elaborated low-molecular-weight library compounds, emphasizing compound quality, ligand efficiency and selected property ranges to keep hits tractable for medicinal chemistry.
• Scope ring systems (ring-X-ring) organize the space and guide intentional functionalization toward low- to mid-micromolar potency; a roughly 10k-compound set suits medium-throughput SPR, native MS, DSF and biochemical screens.
• Case studies on trypanosomal CLK1, a 14-3-3/ERα molecular glue project and SARS-CoV-2 Mpro show comparable primary hit rates to diversity sets, with better ligand efficiency after counter-screening.

The Scope Concept: Defined Chemical Space for Identifying Ligand-Efficient, Tractable Hits Applied to Drug Discovery Targets Trypanosomal CLK1, 14–3–3/Estrogen Receptor-α, and SARS-CoV-2 Mpro ↗

• Pancreatic cancer cells that adapt to KRAS G12D inhibition can be pushed back toward sensitivity by suppressing the JNK pathway more completely.
• Selective covalent inhibitors of MAP2K4, MAP2K7, or both were used to probe how much JNK suppression is needed.
• Stronger JNK blockade disables the feedback loop that reactivates KRAS signaling in resistant cells.
• Inhibitor-sensitive cells gain no benefit, so the vulnerability is specific to the resistant state.

Exploiting Acquired Drug Resistance in Pancreatic Cancer through Selective Covalent Targeting of MAP2K4/7 ↗

• Close ATP-site similarity across class III receptor tyrosine kinases makes selective KIT inhibition hard; this work tackles it with structure-guided optimization.
• A triazolopyridine hinge binder gave a selective start, and a central linker change led to a reverse arylacetamide series with better potency and pharmacokinetics.
• A pyrazole linker and hinge-motif edits kept potency in human serum, while terminal aryl tuning reduced CYP time-dependent inhibition and sharpened kinome selectivity.
• Crystal structures showed that linker stereoelectronics near the gatekeeper can drive selectivity, yielding a lead suited to chronic therapy.

Leveraging Structure-Based Design to Overcome Class III RTK Off-Target Activity in the Development of Selective Wild-Type KIT Inhibitors ↗

• Ion mobility, surface-induced dissociation and variable-temperature ESI were combined to probe BRD4–PROTAC–VCB complexes built with two BET ligands (JQ1 and I-BET726) and PEG linkers of different lengths.
• Shorter linkers held complexes in more extended shapes; longer, flexible linkers allowed relaxed, native-like conformations.
• JQ1 complexes tended to eject the PROTAC under collision, while tighter-binding I-BET726 complexes retained it; the two also melted differently.

Native Mass Spectrometry Reveals Distinct Effects of Linker Length and Targeting-Ligand Identity on PROTAC Ternary Complexes ↗

• Starting from a modest focused-library quinazoline hit, SAR across about twenty analogs gave a chiral lead with sub-micromolar potency and clear selectivity over Nav1.5.
• The absolute configuration was assigned by MicroED, so the active enantiomer is unambiguous without large crystals.
• The lead had acceptable oral exposure, reduced pain behavior in two rodent models, and was clean in a 44-target off-panel; Nav1.7-knockout neuron controls support on-target action.

Discovery of a Quinazoline-Based Nav1.7 Inhibitor with MicroED-Confirmed Absolute Configuration and Oral Efficacy in Rodent Models of Neuropathic Pain ↗

• A perspective reviewing small-molecule inhibitors of the p300/CBP bromodomain and catalytic (HAT) domain, with emphasis on how the leading clinical compounds were optimized.
• It then follows the field's shift toward bifunctional proximity-inducing molecules, including PROTAC degraders.
• The article compares what each modality offers for these large, multidomain coactivators.

Targeting Transcriptional Coactivators p300/CBP: Small-Molecule Inhibitors or Bifunctional Proximity-Inducing Modalities? ↗

• Isoform selectivity within the highly conserved HSP70 family is notoriously hard; the team targeted the peptide-binding pocket of GRP78's substrate-binding domain.
• A direct-to-biology workflow, testing crude library reactions without purification, pointed to compound 12.
• It engages GRP78 in biochemical, biophysical and cellular thermal shift assays, is selective over other tested HSP70s, and perturbs unfolded protein response signaling with selective killing of A549 cells.

Development of Isoform-Selective GRP78 Inhibitors from a Direct-to-Biology Strategy ↗

• Instead of tethering two ligands, the cereblon-binding motif is built into the capping group of an HDAC8 inhibitor, so one structural element engages both proteins.
• Versus the group's first-generation degrader, the compact analogs are smaller, more selective and more drug-like.
• They degrade HDAC8 potently in vivo.

A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗

• Brain delivery is the main barrier for degraders in neurodegeneration; BmTACs attach a macrocyclic peptide shuttle that exploits caveolae-mediated transcytosis, which rises with age in brain endothelium.
• A reactive-oxygen-species-responsive cage on the VHL ligand keeps the PROTAC inactive until it reaches high-ROS tissue.
• The platform is designed to remove activated DAPK1 selectively in the aging brain.

Blood-Brain Barrier-Permeable Macrocyclic Chimeras (BmTACs) for Targeted Protein Degradation in the Aging Brain ↗

• The authors tested whether a co-folding model can replace docking for triage, applying Boltz-2 to the cancer-linked enzyme AKR1B10.
• From a chemically diverse library of 867 candidates, they chose 40 by predicted affinity plus a diversity filter.
• About 70% of those tested showed inhibition at low-micromolar or better, and several submicromolar inhibitors with novel scaffolds emerged.

Efficient Discovery of Potent AKR1B10 Inhibitors Using Co-folding Model Boltz-2 ↗

• EP4 blockade is an immuno-oncology idea built on PGE2-driven immune suppression in tumors.
• Scaffold hopping gave a new chemical series with better activity and pharmacokinetics, and SAR work led to DT-9081.
• It combines potent antagonism, favorable ADME and a clean preclinical safety profile, and has completed a phase I monotherapy trial in solid cancers.

Discovery of DT-9081, a Potent and Orally Bioavailable Small Molecule Antagonist of the EP4 Receptor for the Treatment of Solid Cancers ↗

• Ortho- and meta-substituted aryl sulfamates were synthesized and profiled by thermal shift, enzyme inhibition and a live-cell competition assay against CA IX, the isozyme overexpressed in hypoxic solid tumors.
• The best compounds bound CA IX with very high affinity, and X-ray structures with several isozymes identified the groups driving affinity and selectivity.
• pH-dependent binding data indicate the deprotonated, negatively charged sulfamate nitrogen coordinates the active-site zinc.

Structure-Affinity and Selectivity of Aryl-Sulfamates as Inhibitors of Carbonic Anhydrase IX ↗

• GBA2 has lacked inhibitors that separate it from GBA1 and glucosylceramide synthase; the team built a focused library of electrophilic cyclitols (epoxides, cyclic sulfates, N-alkyl aziridines) from earlier β-D-arabinofuranose activity-based probes.
• Profiling against GBA1, GBA2, GBA3 and glucosylceramide synthase identified covalent inhibitors selective for GBA2.
• The lead is reported as the first brain-penetrant covalent inhibitor to selectively inactivate GBA2 in vivo.

β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors ↗

• Guided by the cryo-EM structure of RXFP4, the authors built a tetrahydroisoquinoline agonist series aimed at two hurdles: close homology to RXFP3 and the need for gut-restricted exposure.
• Lead compound 44 was a potent agonist with strong selectivity over RXFP3 and a pharmacokinetic profile heavily skewed toward ileum over plasma.
• Oral dosing was effective in a loperamide-induced constipation mouse model.

Structure-Guided Discovery of Highly Selective, Gut-Restricted RXFP4 Agonists for the Treatment of Constipation ↗

• SCL-alkyne, a simplified azaphilone derived from the natural product sclerotiorin, was designed to profile lysine reactivity proteome-wide in bacteria.
• It was highly lysine-selective in vitro and in live E. coli; most engaged sites were lysines or protein N-termini, and only a small subset of reactive lysines sat in functional regions.
• Enrichment analysis pointed to bacterial chemotaxis as a major target pathway, which was then confirmed.

Natural product-derived azaphilones are selective scaffolds for covalent lysine liganding in live cells ↗

• Cereblon-recruiting PROTACs are hard to derivatize for prodrug delivery; the paper offers three orthogonal handles: triazole quaternization, tertiary-amine alkylation and a hydroxyl linker.
• The approaches give cleavable prodrugs with tunable release kinetics, compatible with PEGylated constructs and bottlebrush prodrugs.
• Representative examples showed controlled degrader release, in vitro anticancer activity, tumor accumulation and preliminary in vivo efficacy.

Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs ↗

• A Scandinavian consortium built a high-throughput biochemical assay platform for human DNA glycosylases, the eleven enzymes that initiate base excision repair.
• A chemogenomic library was screened against nine glycosylases with assays good enough for hit calling, yielding primary and concentration-response data and several previously unreported inhibitors.
• All data, protocols and metadata are publicly available.

A high-throughput screening dataset of small-molecule inhibitors across human DNA glycosylases ↗

• Melittin is potently antimicrobial but too haemolytic to be a lead; the authors built 10-, 15- and 20-mer peptides from repeats of its C-terminal WIKRK segment.
• The 15- and 20-mers adopt β-sheet structure in bacterial-mimetic vesicles, with negligible haemolysis and cytotoxicity and strong activity against bacteria and mycobacteria.
• They were active in an E. coli mouse infection model by intravenous dosing and inhibited transcription and translation, suggesting an intracellular mechanism.

β-Sheet Antimicrobial and Antimycobacterial Peptides with a High Therapeutic Index by Employing the Repeats of a 5-Mer Segment of α-Helical Cytolytic Melittin ↗

• The team probed the δ-position of the 4,5-dihydroxyisoleucine residue in α-amanitin, a residue long assumed to drive RNA polymerase II inhibition.
• Two δ-modified analogs carry handles for direct linker attachment, so conjugation no longer has to go through other positions on the bicyclic peptide.
• Both were converted into trastuzumab conjugates that showed extremely high cytotoxicity on target-expressing cells, supporting these amatoxins as ADC payloads.

Unlocking Potent Amatoxin Antibody−Drug Conjugates Using Structure−Activity Studies on δ-Substituted-γ-Hydroxy Isoleucine ↗

• Existing αvβ6-targeting tracers for pancreatic cancer suffer from modest tumor uptake and fast washout; the authors varied hydrophilic linkers and an albumin-binding moiety, guided by docking and MD.
• The lead, NOTA-Asp2-IPB-αvβ6L, was labeled with 18F, 68Ga and 177Lu and kept high hydrophilicity, target affinity and albumin binding.
• In PET/CT it showed higher tumor uptake and longer retention while keeping favorable pharmacokinetics, supporting a matched imaging–therapy pair.

Albumin-Binding Modification Improves Tumor Retention of Hydrophilic αvβ6-Targeting Radiotheranostic Tracers ↗

• Tris-catecholate siderophore–meropenem conjugates overcame porin-loss and efflux-based carbapenem resistance in P. aeruginosa in an iron-dependent manner.
• The team also vectorized an indole-carboxylate MBL inhibitor, which alone barely works in P. aeruginosa, apparently for permeability reasons.
• The conjugates restored inhibitor activity and reversed meropenem and cefiderocol resistance in MBL-producing clinical isolates, in vitro and in a Galleria mellonella model.

Siderophore-Enabled Delivery of Carbapenem and Metallo-β-Lactamase Inhibitor: A Promising Strategy against Multidrug-Resistant Pseudomonas aeruginosa ↗

• The authors curated PLAC, an experimentally validated set of ligand activity changes caused by post-translational modifications; affecting PTMs tend to sit closer to the ligand than neutral ones.
• They benchmarked end-point MM/GBSA protocols across MD lengths and internal dielectric constants.
• Longer MD with a higher dielectric gave the best correlation with experiment, while a lower dielectric classified enhance/weaken/neutral better.

Predicting the Post-translational Modification Effects on Protein−Ligand Interactions via End-Point Binding Free Energy Calculation: Database Creation and Strategy Optimization ↗

• An automated, high-throughput ligand-detected NMR method targets hit triage in medicinal chemistry screening campaigns.
• The approach is framed as enabling rapid, qualitative binding assessment of screening hits at scale.
• Reads as a platform/methodology contribution focused on throughput and workflow automation rather than a single target or chemical series.

Automated High-Throughput Ligand-Detected NMR for Medicinal Chemistry Hit Triage and Binding Assessment ↗

• Uses relative binding free energy (FEP-type alchemical) calculations to compare warhead-bearing covalent inhibitors across two related cysteine proteases.
• Cruzain, the key protease of Trypanosoma cruzi (Chagas disease), and human cathepsin L, its close homolog, are modeled in parallel.
• Comparison highlights selectivity for the parasitic target versus off-target reactivity with the human enzyme, guiding optimization.

Assessment of the Binding Affinity of Covalent Inhibitors of Cruzain and Cathepsin L Using Relative Binding Free Energy ↗

• A new series of neutral, heterocyclic-linker-containing transthyretin (TTR) stabilizers is designed for improved brain and cerebrospinal fluid (CSF) penetration.
• Aims to address CNS/leptomeningeal manifestations of hereditary ATTR amyloidosis, where existing acidic stabilizers such as tafamidis show limited CNS exposure.
• Heterocyclic linker modifications reduced compound acidity relative to earlier chemotypes while reportedly preserving TTR tetramer-stabilizing potency and selectivity in vitro.

Discovery of Neutral and Cerebrospinal Fluid Penetrant Transthyretin (TTR) Stabilizers with Heterocyclic Linkers ↗

• A direct-to-biology (D2B) platform synthesizes candidate compounds at small scale and evaluates the crude reaction mixtures directly in biological assays, bypassing conventional purification.
• The approach couples miniaturized, automation-compatible chemistry with rapid biological readout to shorten the design-make-test cycle typical of early hit-finding and library exploration.
• Positioned within a broader wave of D2B methodology in medicinal chemistry, applicable to accelerating hit identification across diverse chemotypes.

Direct-To-Biology Platform Enabled Drug Discovery ↗

• Perspective-style article proposing that pharmacological inhibition of the epigenetic enzyme LSD1 (KDM1A) can modulate cellular sensitivity to nucleoside analogue therapeutics.
• Synthesizes evidence across myeloid malignancies and viral infections, two disease areas where nucleoside analogues are already established treatments.
• Argues LSD1-driven chromatin and transcriptional changes may underlie altered drug response, positioning LSD1 inhibitors as potential combination partners to enhance nucleoside analogue efficacy across both fields.

Targeting LSD1 Modulates Therapeutic Responses to Nucleoside Analogues: From Myeloid Malignancies to Viral Infections ↗

• Iron-binding chemistry anchors a new bacteria-targeted imaging probe engaging MurB, an enzyme unique to bacterial peptidoglycan (cell-wall) biosynthesis, for radiolabeling.
• The probe is proposed as a platform for PET (positron emission tomography), aiming to visualize actual bacterial infection sites in vivo rather than relying on nonspecific inflammation markers.
• By targeting a pathway absent in human cells, the approach could help clinicians distinguish genuine bacterial infection from sterile inflammation, addressing a longstanding gap in infectious-disease imaging.

Leveraging the Iron-Probe-MurB Interaction: An Enhanced Platform for PET Imaging of Bacterial Infections ↗

• Poly(disulfide)s are dynamic-covalent polymers whose guanidinium-rich chains cross cell membranes via thiol-mediated uptake, engaging surface thiols rather than classical endocytosis.
• This study probes the chemical basis of that uptake, linking polymer structure and disulfide exchange to membrane translocation and cytosolic release.
• It reinforces poly(disulfide)s as a macromolecular delivery modality for proteins, antibodies, and nucleic acids, bypassing lysosomal degradation.

The Nature of Cell‐Penetrating Poly(disulfide)s ↗

• A two-step route builds covalent genetically-encoded macrocycle libraries (cGELs): cysteines form the macrocycle via a diketone linchpin, then a separate Knorr-pyrazole step adds the electrophilic warhead.
• Separating cyclization (basic pH) from warhead installation (acidic pH) avoids the regioisomer mixtures that limited earlier one-pot chemical modification methods.
• This lets more diverse, reactive electrophiles be used safely, broadening covalent chemotypes accessible for selections against protein targets in DEL-style screens.

A Two-Step Synthesis of Covalent Genetically Encoded Libraries of Peptide-Derived Macrocycles Enables the Use of Electrophiles with Diverse Reactivity ↗

• A new series of fluorinated 4-methylideneisoxazolidin-5-one derivatives adds fluorine substituents onto the exocyclic methylidene-lactone-type isoxazolidinone core.
• The fluorinated analogs showed antiproliferative activity against cancer cell lines, with the reported cell-death mechanism attributed to induction of apoptosis.
• Structure-activity comparisons across the fluorinated series highlighted substitution patterns linked to improved potency and selectivity relative to non-fluorinated parent compounds.

Fluorinated 4-Methylideneisoxazolidin-5-ones: Synthesis and Apoptosis-Inducing Antiproliferative Activity ↗

• Imidazolium amino acids are proposed as cationic bioisosteres mimicking the size and charge of trimethyllysine, dimethylarginine, and arginine side chains.
• Binding to methyl-lysine reader domains is evaluated to see how closely the surrogates reproduce native residue recognition and selectivity.
• Cell assays indicate the charged isosteres can still traverse membranes, and SAR trends tie ring substitution to the affinity-permeability tradeoff for reader ligands and CPPs.

Evaluation of Binding and Cell Penetration of Imidazolium Amino Acids as Novel Bioisosteres for Trimethyllysine, Dimethylarginine, and Arginine ↗

• Researchers built a live-cell NanoBRET assay to test whether reported p53 Y220C ligands truly engage the mutant protein inside intact cells.
• The BRET-based readout gives a cell-based engagement ranking for known Y220C stabilizer/reactivator compounds, complementing prior biochemical binding data.
• Such cellular validation checks permeability and intracellular target occupancy, a key hit-to-lead checkpoint for this hard-to-drug p53 cavity mutant.

NanoBRET Target Engagement Enables Validation of p53 Y220C Ligands in a Cellular Context ↗

• Researchers used structure-guided design to develop a covalent small-molecule inhibitor of human butyrylcholinesterase (BChE), an enzyme increasingly implicated in Alzheimer's disease progression.
• The lead compound was engineered for blood-brain barrier penetration, a key hurdle for centrally acting cholinesterase inhibitors.
• In vivo testing showed procognitive efficacy, supporting covalent BChE inhibition as a potential treatment approach for Alzheimer's disease.

Structure-Guided Design of a Brain-Penetrant Covalent Inhibitor of Human Butyrylcholinesterase with In Vivo Procognitive Efficacy ↗

• Medicinal chemists designed single small molecules combining PARP inhibition with GPX4 inhibition, pairing DNA-repair blockade with ferroptosis induction in one compound rather than as a drug combination.
• Structure-activity relationship work identified a new dual-acting chemotype optimized for potency against both targets.
• Lead compounds showed antitumor activity in triple-negative breast cancer models, supporting the dual-mechanism approach as a possible way to broaden PARP inhibitor efficacy.

Discovery of Dual PARP/GPX4 Inhibitors for the Treatment of Triple-Negative Breast Cancer ↗

• Exelixis researchers optimized an aminopyrazole hit series targeting PLK4, a kinase essential for centriole duplication, culminating in the advanced compound EXEL-1855.
• Structure-guided SAR and selectivity profiling addressed off-target kinase liabilities that had limited earlier aminopyrazole PLK4 inhibitors such as centrinone.
• In preclinical tumor models, EXEL-1855 showed strong antitumor activity, supporting its selection as a development candidate.

Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy ↗

• A pocket-conditioned, autoregressive generative AI model was used to design candidate molecules directly within the STAT3 binding pocket, rather than screening pre-existing compound libraries.
• This structure-based generative approach produced a potent small-molecule STAT3 inhibitor that advanced to biological evaluation.
• The inhibitor showed activity against colorectal cancer, where STAT3 hyperactivation is a recognized driver of tumor growth and survival.

Pocket-Conditioned Autoregressive Molecular Generative Algorithm-Driven Discovery of a Potent STAT3 Inhibitor for Colorectal Cancer Treatment ↗

• Researchers built ionizable lipid nanoparticles with fluorinated lipid tails to encapsulate and deliver a PROTAC degrader payload.
• Tuning the degree of fluorination altered nanoparticle physicochemical properties and redirected intracellular trafficking, promoting more efficient endosomal escape into the cytosol.
• Optimized fluorinated formulations achieved greater cytosolic PROTAC release and stronger target-protein degradation than non-fluorinated lipid controls.

Fluorination-Tuned Ionizable Lipids Regulate Nano-PROTAC Trafficking for Enhanced Targeted Protein Degradation ↗

• Chemists built fluorinated Tn-antigen mimics using a tyrosine-linked GalNAc (Tyr-GalNAc) instead of the natural serine/threonine attachment, then conjugated them to bacteriophage Qβ virus-like particles.
• Qβ is a multivalent carrier platform known for driving strong antibody responses to small carbohydrate tumor antigens.
• The fluorinated Tyr-GalNAc-Qβ conjugates showed potent antitumor activity in preclinical models, adding to evidence that targeted fluorination can boost carbohydrate-antigen vaccine immunogenicity.

Synthesis of Fluorinated Tyr-GalNAc Antigens and Potent Antitumor Activity of Their Bacteriophage Qβ Conjugates ↗

• A new PROTAC degrader targets STAT6, the transcription factor that carries IL-4/IL-13 signals driving Th2-type allergic inflammation.
• Instead of inhibiting STAT6, the molecule links a STAT6-binding fragment to a degradation handle for potency and selectivity over related STAT proteins.
• It reportedly showed oral efficacy in preclinical models, pointing to a pill-based alternative to injectable biologics for atopic dermatitis.

Discovery of a Potent, Selective, and Orally Efficacious STAT6 PROTAC for the Treatment of Atopic Dermatitis ↗

• A new bioRxiv preprint investigates how the chemical architecture of antibody-oligonucleotide conjugates (AOCs) affects their performance as siRNA delivery vehicles.
• The work examines design variables such as linker composition, conjugation site on the antibody, and siRNA chemical modification pattern.
• Findings aim to clarify which structural choices most influence knockdown potency and delivery efficiency, informing rational AOC design.

Enhancing the efficacy of siRNA Antibody Oligonucleotide Conjugates (AOCs) through chemical design ↗

• Alliin, a natural cysteine-sulfoxide that chelates BACE-1's catalytic dyad, has poor pharmacokinetics, limiting its use as a drug lead.
• Researchers used a fragment-growing strategy guided by molecular dynamics simulations to build out from this core, aiming to improve affinity and drug-like properties.
• The campaign remains an early-stage computational effort, not a validated clinical candidate.

Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics ↗

• Bayesian flow networks design molecules for protein pockets by jointly generating atom types and 3D coordinates.
• The two channels behave differently: atom types shift abruptly at a defined point, while coordinates sharpen gradually, a pattern consistent across model variants.
• Timing refinement to these transition points yields a training-free method matching baseline docking performance on a standard benchmark, with no extra predictor needed.

Hierarchical Phase Transitions in Bayesian Flow Networks Enable Training-Free Molecular Design ↗

• Scientists converted an F2Pmp-based dual PTP1B/TCPTP inhibitor into a CRBN-recruiting bifunctional degrader, named X1.
• X1 shows improved potency, selectivity, and plasma exposure after intraperitoneal dosing versus earlier tools.
• Degrading both phosphatases boosts TCR signaling in T cells and IFNγ-driven JAK/STAT1 signaling in tumor cells, raising MHC-I antigen presentation.
• In a mouse tumor model, X1 alone or with anti-PD-1 increased T cell infiltration/activation and drove robust anti-tumor efficacy.

Discovery and Characterization of a Cereblon-Based Degrader for PTP1B and TCPTP ↗

• A new method systematically edits SMILES strings—swapping atom types, resizing or opening rings, and grafting fragments—to generate analog ideas for fragment-to-lead optimization.
• First implemented as a KNIME workflow tested on fragments from multiple programs, it's now also available as open-source Python code paired with AutoDock Vina docking.
• This non-learned, rule-based approach complements AI/ML generative design, offering a practical option when training data for a target is scarce.

Fragment Optimization─Simple SMILES String Manipulation Strategies to Optimize a Hit or Fragment ↗

• An earlier pyrazole-based CDK2 inhibitor scaffold was computationally redesigned around an imidazole core to improve selectivity over CDK1.
• The new chemotype was optimized simultaneously for potency, CDK1/CDK2 selectivity, and physicochemical properties.
• This work yielded INCB127443, an orally bioavailable candidate with favorable CDK1 selectivity and a flat pharmacokinetic profile enabling sustained in vivo target coverage.

Discovery of INCB127443: A Potent and Orally Available Inhibitor of Cyclin-Dependent Kinase 2 ↗

• SHP2 is a cytosolic protein tyrosine phosphatase implicated in oncogenic RTK and immune checkpoint signaling, making it a closely watched cancer/immuno-oncology target.
• Earlier allosteric SHP2 inhibitors have reached clinical trials but can face resistance mutations or PK limitations, motivating further chemotype exploration.
• This preprint reports a new series of N-aryl-1H-azaindole-derived allosteric SHP2 inhibitors, shifting away from orthosteric (active-site) inhibition approaches.

Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric SHP2 inhibitors ↗

• Two-step triazole stapling built a peptide from DN-9's opioid segment, then added an NPFF pharmacophore via chimeric conjugation to form a multitarget agonist.
• The opioid-only stapled peptide acts as a μ-opioid agonist with partial δ-opioid activity; the conjugate targets μ-, κ-opioid and NPFF receptors with G-protein-biased μ signaling.
• Subcutaneous dosing of both compounds produced sustained, dose-dependent analgesia in acute and visceral pain models.

Two-Step Design of Triazole-Stapled Opioid Agonists Exhibiting Potent and Prolonged Peripheral Analgesic Activity ↗

• TrmD, a SPOUT-family bacterial tRNA methyltransferase without a human counterpart, is highlighted as a validated antibacterial target amid rising antimicrobial resistance.
• The review catalogs strategies used to discover small-molecule TrmD inhibitors—fragment-based design, high-throughput and virtual screening, click-chemistry-enabled direct-to-biology methods, molecular hybridization, and prodrug approaches.
• It synthesizes structural features and structure-activity relationships across these diverse chemical scaffolds to inform future inhibitor optimization.

TrmD: A Promising Antibacterial Target and Its Small-Molecule Inhibitors ↗

• Building on the TRPM7 blocker NS8593, researchers created a set of 2-aminobenzimidazole analogues and identified two standout leads, SDUY212 and SDUY225, validated by electrophysiological recordings.
• Both compounds slowed growth, migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells and triggered apoptosis and cell-cycle arrest; SDUY212 also shrank tumors in xenograft-bearing mice.
• The anti-invasive effect appeared linked to reduced EGF-triggered STAT3 activation downstream of TRPM7.

Design, Synthesis and Biological Evaluation of New TRPM7 Channel Inhibitors as Potential Therapeutics for Breast Cancer ↗

• Research highlight on a stereoselective, cysteine-reactive molecule that locks the pro-apoptotic protein BAX into an inactive shape, blocking programmed cell death.
• Optimization yielded a lead compound suitable for in vivo dosing that limited liver-cell death and preserved organ function in a mouse model of acute liver injury.
• It also protected stem-cell-derived motor neurons from healthy and ALS-patient donors, pointing to wider relevance in neurodegenerative disease.

Covalent BAX inhibitor confers cytoprotection ↗

• Commentary piece examining the rapid growth of make-on-demand virtual compound libraries, now spanning tens of billions of molecules, and the practical challenges this scale poses for computational screening.
• Discusses how researchers prioritize and search these vast chemical spaces efficiently, weighing computational cost against the risk of overlooking promising hits.
• Considers how such large-scale screening approaches fit into early-stage hit-finding workflows in drug discovery.

Navigating ultralarge virtual screening ↗

• Applies a hotspot-centric computational design strategy, grafting key antibody-binding side chains onto small L-peptide scaffolds that mimic how neutralizing antibodies engage influenza hemagglutinin.
• Draws design cues from the antigen-binding interfaces of broadly neutralizing antibodies FI6v3 and CR9114, both directed at the hemagglutinin stem.
• Aims to yield peptides that block the hemagglutinin conformational change driving membrane fusion, offering a structure-guided route to antibody-inspired flu therapeutics.

Antibody Hotspot-Centric de Novo Design of Peptide Inhibitors of Influenza A Virus Membrane Fusion ↗

• Compares physics-based docking, deep-learning co-folding, and hybrid rescoring methods on how well they generalize to unfamiliar protein targets and chemical scaffolds.
• Builds on the recent Runs-n-Poses benchmark, which found that classical physics-based docking held an edge over several co-folding tools on truly novel targets.
• Assesses pose accuracy and ranking performance to offer practical guidance on choosing a docking strategy based on target novelty.

Multiparadigm Benchmark of Molecular Docking: From Physics to Co-Folding and Hybrid Models ↗

• Reports a new series of caspase-1-targeting small molecules built on a dihydropyridine scaffold, a heterocyclic chemotype more commonly associated with calcium-channel drugs.
• Characterizes inhibitory activity with in vitro fluorescence-based enzymatic assays and extends the work into cell-imaging studies of caspase-1 activity.
• Positions the compounds as early leads given caspase-1's central role in inflammasome-driven inflammatory signaling.

Potent Caspase-1 Antagonists From Dihydropyridine Derivatives: In Vitro Fluorescence Assays and Cell Imaging ↗

• Starts from known capsid assembly modulator NVR 3-778 and applies a multi-objective optimization workflow combining structure-based fragment growing with medicinal chemistry.
• Machine-learning models are used alongside traditional design to jointly predict antiviral activity and drug-like/ADMET properties.
• The workflow generated and evaluated roughly four dozen novel sulfamoylbenzamide analogs.
• Lead compound 11B-6 emerged with superior antiviral potency and improved drug-like properties versus the starting scaffold.

Integrated AI-Driven Multi-Objective Optimization of Sulfamoylbenzamide-Based HBV Capsid Assembly Modulators: Discovery of 11B-6 with Superior Potency and Drug-like Properties ↗

• Second-generation analogs of the first-in-class caPCNA-selective inhibitor AOH1996, built by systematically modifying each of its four pharmacophoric regions.
• Explored substituent changes, bioisosteric swaps, linker adjustments, and scaffold hopping to improve on the parent compound.
• Lead analogs showed markedly improved cancer cell potency and better liver microsomal metabolic stability than AOH1996.
• Compounds were profiled across multiple cancer cell lines, including neuroblastoma and breast/colorectal cancer models.

Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA ↗

• Targets CK1δ, an upstream kinase that stabilizes oncogenic NRAS mutant protein, as an indirect strategy against NRAS-driven melanoma.
• Reports discovery of compound 8u, a selective small-molecule degrader rather than a simple catalytic inhibitor.
• The degrader approach achieves high selectivity for CK1δ over closely related CK1 isoforms, addressing a limitation of earlier inhibitors.
• Treatment destabilizes mutant NRAS protein and suppresses oncogenic signaling in melanoma models.

Discovery and Synthesis of Selective Casein Kinase 1δ Degraders for Suppressing Oncogenic NRAS-Mutant Melanoma ↗

• Builds on a prior azaindole-quinazoline lead compound and addresses its limited blood-brain barrier penetration.
• Uses an intramolecular cyclization strategy to mask a hydrogen-bond-donating amine group that was prone to P-glycoprotein-mediated efflux.
• Resulting analogs retain strong DYRK1A inhibitory activity while markedly improving brain exposure.
• Optimized compounds reduce microglia-driven neuroinflammatory markers in disease-relevant models.

Brain Penetration Optimization and Anti-neuroinflammation Evaluation of Potent 6-Methyl-7-azaindol-3-yl-quinazoline DYRK1A Inhibitors for Alzheimer's Disease ↗

• A conspectus recounting a research program to design small-molecule inhibitors of human pancreatic α-amylase, key to starch digestion and post-meal glucose spikes.
• Frames the work against the rising global burden of type 2 diabetes and its glycemic complications.
• Traces iterative structure-based design that pushed inhibitor affinity from nanomolar into the picomolar range.
• Discusses translational potential of these ultra-potent inhibitors for managing postprandial hyperglycemia.

Discovery, Design, and Evaluation of Nanomolar to Picomolar Inhibitors of Human Pancreatic α-Amylase for Control of Postprandial Blood Glucose Levels ↗

• A new series of dihydropyridine-derived small molecules is reported as antagonists of caspase-1, a cysteine protease central to inflammasome signaling.
• Caspase-1 activation drives maturation of the pro-inflammatory cytokines IL-1β and IL-18, making it a longstanding target in inflammation and inflammasome-related disease research.
• The dihydropyridine scaffold, more commonly associated with calcium-channel pharmacology, is explored here as a chemotype for caspase-1 antagonism.
• Compound activity was characterized using in vitro fluorescence-based enzymatic assays to gauge caspase-1 antagonism.
• Cell imaging was used alongside the biochemical assays to examine compound behavior and target engagement in a cellular context.
• The study, published in ChemMedChem, presents this dihydropyridine series as a structure-activity starting point for further caspase-1/inflammasome-directed medicinal chemistry.

Potent Caspase-1 Antagonists From Dihydropyridine Derivatives: In Vitro Fluorescence Assays and Cell Imaging ↗

• PCNA supports at least 11 cellular pathways in DNA replication and repair; tumor cells express a distinct acidic isoform (caPCNA) not found in normal cells, creating a potential cancer-selective drug target.
• AOH1996 is City of Hope's first-in-class small-molecule PCNA inhibitor, which binds the PIP-box pocket to disrupt caPCNA protein interactions and selectively kill malignant cells.
• This paper describes second-generation AOH1996 analogues built through systematic structure-activity relationship work (substituent changes, bioisosteric replacement, linker and heteroatom modification, scaffold hopping) across all four pharmacophore regions.
• Lead analogues showed improved cellular potency against multiple cancer cell lines and better liver microsomal stability than first-generation AOH1996, supporting further lead optimization of this PCNA-targeted chemotype.

Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA ↗

• Building on prior work identifying CK1δ as an upstream stabilizer of oncogenic NRAS, the team developed small-molecule degraders that trigger CK1δ's proteasomal breakdown.
• Chemical optimization focused on achieving selectivity for CK1δ over its close paralogs CK1α and CK1ε, which share highly similar kinase domains.
• Iterative structure-activity relationship analysis across a synthesized compound series balanced degradation potency, isoform selectivity, and cellular activity.
• Degrading CK1δ removed its support for oncogenic NRAS protein stability, lowering NRAS levels and dampening downstream signaling in melanoma cells.
• In NRAS-mutant melanoma cell models, the optimized degraders suppressed proliferation, positioning CK1δ degradation as a potential strategy for an otherwise hard-to-drug oncogenic driver.

Discovery and Synthesis of Selective Casein Kinase 1δ Degraders for Suppressing Oncogenic NRAS-Mutant Melanoma ↗

• The study benchmarks machine learning, physics-based docking, and cofolding methods for predicting protein-ligand binding using DNA-encoded library (DEL) screening data.
• Methods compared include state-of-the-art ML models alongside physics-based docking tools (Schrodinger Glide, Rosetta GALigandDock) and the cofolding method Boltz-2.
• Ground-truth binding data came from ultralarge DEL selection experiments across three biologically diverse protein targets and multiple DEL synthesis formats.
• The work follows a NeurIPS competition in which even top-performing ML models trained on DEL data failed to generalize to out-of-distribution (OOD) chemical space.
• ML models performed well in-distribution, but out-of-distribution hit discrimination depended on the specific target and ligand context, with no single method consistently dominating across cases.
• The authors conclude that benchmark performance alone cannot predict OOD generalization and release an open-source package, DEL-iver, for evaluating binding-prediction methods against DEL screening data.

Assessing the Generalizability of Machine Learning and Physics-Based Methods with DNA-Encoded Libraries ↗

• Investigators describe a multi-objective lead-optimization campaign built on the sulfamoylbenzamide (SBA) chemotype exemplified by NVR 3-778, an earlier clinical-stage HBV capsid assembly modulator (CAM).
• An AI-guided computational workflow was integrated with iterative synthesis to simultaneously optimize antiviral potency alongside physicochemical and ADME/drug-like properties across the series.
• The campaign identified 11B-6 as the optimized lead, reported to combine stronger anti-HBV potency with improved drug-like characteristics relative to earlier series analogues.
• Mechanistically, 11B-6 functions as a capsid assembly modulator, engaging the HBV core (capsid) protein to misdirect nucleocapsid assembly and interfere with viral replication.
• The work positions 11B-6 as a candidate for further preclinical evaluation within the sulfamoylbenzamide CAM class for chronic hepatitis B treatment.

Integrated AI-Driven Multi-Objective Optimization of Sulfamoylbenzamide-Based HBV Capsid Assembly Modulators: Discovery of 11B-6 with Superior Potency and Drug-like Properties ↗

• Rhinitis is a heterogeneous upper-airway inflammatory condition whose chronic symptoms, especially in mixed and nonallergic disease, often resist first-line intranasal antihistamines and corticosteroids.
• The authors designed bifunctional small molecules combining muscarinic M3 antagonism, which limits glandular hypersecretion and rhinorrhea, with histamine H1 antagonism, which limits itch, sneezing and vasodilation.
• A structure-activity relationship campaign balanced potency at both receptors within a single scaffold while extending duration of action, targeting once-daily control rather than short-acting relief.
• Lead compounds were profiled for pharmacokinetics, receptor selectivity and safety, distinguishing this dual-target strategy from conventional single-mechanism antihistamines or anticholinergics.
• This positions combined M3/H1 antagonism as a candidate approach for rhinitis, including mixed and nonallergic forms, poorly controlled by existing monotherapies.

Discovery of Long-Acting Bifunctional Compounds with Muscarinic M3 and Histamine H1 Receptor Antagonism for the Treatment of Rhinitis ↗

• Researchers designed a new class of small molecules built on a benzothieno[3,2-d]pyrimidin-4(1H)-one scaffold that simultaneously inhibits PARP-1 and casein kinase 2 alpha (CK2α).
• PARP-1 inhibitors typically benefit only tumors with homologous recombination deficiency (HRD); pairing PARP-1 blockade with CK2α inhibition, a kinase linked to DNA damage response and cell survival signaling, is proposed to extend efficacy to HRD-proficient tumors and limit metastatic spread.
• Structure-activity relationship exploration identified substituents on the tricyclic core that support potent, balanced binding at both targets.
• In cellular and tumor models, the dual inhibitors reportedly show antiproliferative and anti-metastatic activity independent of HRD status, supporting dual-target inhibition as a route beyond BRCA-mutant-restricted use.

Simultaneous Inhibition of PARP-1 and CK2α by Novel Benzothieno[3,2-d]pyrimidin-4(1H)-one Derivatives: A Promising Strategy to Combat Homologous Recombination Deficiency-Independent Tumors and Metastasis ↗

• PROTACs (proteolysis-targeting chimeras) are large, polar, conformationally flexible molecules that fall outside classical Rule-of-5 space, making oral absorption difficult to predict from standard physicochemical filters alone.
• The paper introduces a fully computational scoring approach for oral absorption, intended to support rational, in silico PROTAC design earlier in the discovery process rather than relying mainly on measured properties.
• The score is built from computed molecular descriptors likely spanning size, polarity/lipophilicity balance, flexibility, and conformational behavior such as intramolecular folding — features previously linked to permeability in beyond-Rule-of-5 compounds.
• By combining these descriptors into a single predictive metric, the method aims to help chemists rank or triage PROTAC candidates for oral-absorption potential before synthesis.
• The authors position the score as a practical design-stage tool for guiding linker, warhead, and E3-ligand modifications toward improved oral bioavailability, complementing rather than replacing experimental permeability assays.

Toward Rational Design of Orally Bioavailable PROTACs: Development of a Fully Computational Oral Absorption Score ↗

• Hydroxamic acid-based HDAC inhibitors are limited by poor selectivity among metalloenzymes and by genotoxicity risk linked to isocyanate metabolites.
• The study applies a previously reported iron(II)-activatable conjugate platform to cage the pan-HDAC inhibitor panobinostat, aiming for tumor-conditional payload release.
• In multiple myeloma cell line models, the conjugate successfully caged HDAC inhibitory activity, and a bioisosteric control conjugate showed reduced genotoxicity relative to the free hydroxamate.
• Follow-up investigation identified the carboxylesterase CES1 as responsible for unexpected proteolytic instability of the panobinostat conjugate observed both in vitro and in vivo.
• The finding is noted as a focus for future work toward mitigating hydroxamate-associated toxicity and mutagenicity through more robust tumor-conditional activation.

Toward Tumor-Conditional Release of Histone Deacetylase Inhibitors from Nongenotoxic Drug Conjugates ↗

• Researchers developed REAPS, a geometric graph neural network for designing peptide binder sequences that models the target receptor as a fully observable, all-atom structural context, rather than relying on backbone geometry alone as typical inverse-folding methods do.
• In head-to-head evaluations against the widely used inverse-folding model ProteinMPNN, REAPS showed improved sequence recovery, structural fidelity, and interface-level biophysical properties for both linear and macrocyclic peptide binders.
• The team paired REAPS with structural hallucination in a closed-loop de novo design pipeline to generate novel peptide candidates without requiring a known starting scaffold.
• Candidates produced through this pipeline were synthesized and tested against the neurokinin-3 receptor (NK3R), where they showed experimentally confirmed functional activity.

REAPS: An All-Atom Receptor-Aware Geometric Deep Learning Framework for De Novo Design of Linear and Macrocyclic Peptide Binders ↗

• Researchers developed Hsc70-Mediated Targeting Chimeras (Hsc70TACs), bifunctional small molecules that link an Hsc70-binding ligand to a ligand for a protein of interest, directing target degradation through chaperone-mediated autophagy rather than the ubiquitin-proteasome pathway used by PROTACs.
• The approach is proposed to extend the range of degradable targets, including certain cytosolic and cell-membrane proteins, and to offer an alternative route that may help address resistance risks associated with proteasome-dependent degraders.
• Degradation activity was demonstrated across multiple protein classes, including the transcriptional regulator BRD4, the regulatory protein MDM2, and the cell-membrane immune checkpoint protein PD-L1, across diverse cellular contexts.
• A lead BRD4-directed compound, B-2, showed favorable pharmacokinetic behavior and produced robust BRD4 degradation in vivo, supporting continued development of the Hsc70TAC modality.

Hsc70-Mediated Targeting Chimeras for Targeted Protein Degradation via Chaperone-Mediated Autophagy ↗

• NaV1.8 inhibition is a clinically validated non-opioid strategy for pain, with the marketed drug VX-548 (Journavx) serving as the benchmark; its metabolic pathways in humans and rats are well characterized.
• Researchers designed a new chemotype, 2-(2-benzimidazole)-substituted tetrahydrofurans, and applied structure-based optimization to circumvent VX-548's known metabolic liabilities while retaining nanomolar NaV1.8 potency and subtype selectivity.
• The resulting lead, compound 31, showed favorable oral bioavailability in rats, with plasma AUC more than 10-fold higher than VX-548, alongside potent in vivo analgesic efficacy.
• Pharmacokinetic behavior was consistent across species, with favorable profiles also seen in beagle dogs and cynomolgus monkeys.
• Compound 31 exhibited a favorable early safety profile, including no genotoxicity and weak hERG inhibition, supporting its status as a metabolically optimized preclinical lead for further evaluation.

Discovery of Novel 2-(2-Benzimidazole)-Substituted Tetrahydrofurans as Potent and Selective NaV1.8 Inhibitors for the Treatment of Pain ↗

• Approved PI3Kα inhibitors for HR+/HER2− PIK3CA-mutated breast cancer cause dose-limiting hyperglycemia and other adverse effects linked to inhibition of wild-type PI3Kα.
• Researchers designed a series of tetrasubstituted quinazolin-4(3H)-one compounds intended to selectively inhibit the oncogenic PI3Kα H1047R mutant.
• Selectivity for the mutant enzyme over wild-type PI3Kα is proposed to stem from a slow-on, slow-off binding mechanism.
• Lead compound 34 showed potent, mutant-selective activity in vitro along with a favorable ADME profile.
• In a T47D xenograft mouse model, compound 34 produced significant tumor growth inhibition without affecting blood glucose or serum insulin levels, unlike a benchmark approved PI3Kα inhibitor.
• The authors note that further optimization of compound 34 is needed to lower the efficacious dose and improve tolerability.

Discovery of Tetrasubstituted Quinazolin-4(3H)-ones as Wild-type-sparing, Highly Selective PI3Kα H1047R Inhibitors ↗

• Researchers built a combined screening pipeline pairing covalent fragment screening with a ligand-first design strategy to find chemical matter that reacts with lysine side chains rather than the more commonly targeted cysteines.
• The work focuses on the allosteric "latch" region of SHP2 phosphatase, a regulatory site distinct from the enzyme's catalytic pocket and from previously drugged allosteric tunnel sites.
• Computational modeling and experimental characterization were used together to guide fragment selection and to understand how covalent attachment at latch-site lysines affects the protein's conformational behavior.
• The approach yielded inhibitors described as the first potent, cell-active covalent compounds acting through this latch site, indicating the pocket can support functional, drug-like engagement rather than only structural characterization.
• The findings position lysine-directed covalent chemistry as a viable route for allosteric SHP2 modulation and provide a starting chemotype and site for further medicinal chemistry optimization.

Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗

• Researchers designed VHL-recruiting PROTAC degraders targeting EGFR, aiming to overcome acquired resistance to conventional EGFR kinase inhibitors in non-small cell lung cancer (NSCLC).
• Lead compounds C4 and D4 achieved potent, selective, and durable degradation of the EGFR Del19 and L858R resistance mutants.
• C4 induced cell cycle arrest and apoptosis, showed subnanomolar antiproliferative activity, and produced significant tumor regression in an HCC827 xenograft model at low intravenous doses on a reduced twice-weekly schedule.
• D4 was orally bioavailable and blood-brain barrier penetrant, and oral dosing completely halted tumor growth in vivo.
• The findings support a degradation-based strategy, rather than conventional inhibition, as a route to next-generation EGFR-directed therapies with potential central nervous system relevance.

Discovery of Potent and Selective VHL-Recruiting PROTAC Degraders Targeting EGFR with Improved Developability and Potent Anti-NSCLC Efficacy ↗

• Five new natural products, hyreptaones A-E (1-5), were isolated from the plant Hypericum reptans, defining a novel class of 1,2-seco-bicyclic polyprenylated acylphloroglucinols (BPAPs).
• Compounds 1-3 are the first 1,2-seco-BPAPs shown to derive from rare 3,3-diisoprenylated BPAP precursors, while 4 and 5 feature an unusual spirocyclic 6/5/5 ring system formed by further cyclization of the 1,2-seco-BPAP core.
• Structures were established using spectroscopic analysis together with X-ray crystallography.
• All five compounds preferentially inhibited the Cav3.1 T-type calcium channel over other T-type channel subtypes, indicating isoform selectivity.
• Compounds 4 and 5 additionally showed state-dependent modulation of Cav3.1 gating, marking them as a new class of Cav3.1 allosteric modulators.

1,2-seco-Bicyclic Polyprenylated Acylphloroglucinols as Isoform Selective Inhibitors of T-Type Calcium Channels ↗

• Researchers built Ctx-ETAC, a degrader-antibody conjugate pairing the approved EGFR antibody cetuximab with an engineered PROTAC payload, attached via a bioorthogonal reaction at a defined, controlled ratio per antibody.
• Its PROTAC payload pairs an indomethacin-derived COX-2 ligand with a VHL-recruiting peptide via a cathepsin B-cleavable linker, releasing the degrader selectively inside EGFR-positive tumor cells and activated fibroblasts.
• Degrading COX-2 in both cell types substantially curtails extracellular vesicle secretion, severing a key tumor-stroma signaling channel and nudging fibroblasts toward a quiescent, less tumor-supportive state.
• In a lung cancer xenograft model, Ctx-ETAC outperformed cetuximab alone in restraining tumor growth without added systemic toxicity, supporting microenvironment-targeted degradation as a therapeutic strategy.

Receptor-Guided Targeted Protein Degradation Collapses Extracellular Vesicle-Driven Tumor-Stroma Crosstalk ↗

• Multi-stage virtual screening cascades that combine AI co-folding models with learned-affinity (ML) scoring are now standard practice in computational drug discovery.
• Each stage's output score is typically taken at face value and used to advance or discard candidates without independent validation of what it actually captures.
• This preprint systematically evaluates, stage by stage, whether cascade scores provide the information practitioners need to trust them, using the Keap1-Nrf2 protein-protein interaction as a case-study target.
• The authors characterize failure modes that arise at different stages of the cascade, offering a quality-control perspective on where and why these pipelines can mislead.

Per-Stage Controls and Failure Modes in a Co-Folding Virtual Screening Cascade for the Keap1–Nrf2 Interaction ↗

• More than 300 X-ray cocrystal structures spanning diverse kinase-inhibitor complexes were analyzed to catalog recurring non-covalent contact patterns.
• The study highlights a set of conserved Lys, Asp, and Glu residues near the ATP pocket, dubbed "Catalytic Cluster Residues" (CCRs), that support catalysis and frequently contact bound inhibitors.
• Across most inhibitor chemotypes, these polar residues form non-covalent interactions rather than covalent bonds, making them broadly relevant handles for ligand design.
• Side-chain orientation of the CCRs tracks with the kinase's active or inactive conformational state, linking binding geometry to structural dynamics.
• The authors argue this conformation-coupled behavior can guide rational, structure-based inhibitor design aimed at improving potency and tuning selectivity across the kinome.

A Structural Perspective on Non-covalent Targeting of Conserved Polar Residues in Protein Kinases ↗

• Omaveloxolone is an FDA-approved Nrf2-activating drug, originally approved for Friedreich's ataxia, now repurposed as a STING-targeting agent.
• It binds the base of STING's ligand-binding domain, destabilizing the protein's folded structure.
• This triggers K27-linked polyubiquitination of STING and its subsequent degradation by the proteasome — a "molecular crowbar" mechanism.
• Unlike classical PROTAC-style bifunctional degraders, omaveloxolone acts as a single small molecule, directly destabilizing STING rather than using a ligand-linker-E3-ligase construct.
• In aged mice, omaveloxolone treatment reduced STING-pathway-driven inflammation, a hallmark of age-related "inflammaging."

Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation ↗

• HDAC4 and HDAC7 — two class IIa histone deacetylases with tissue-restricted expression — were recently identified as distinct transcriptional drivers of Th17 cell differentiation.
• Using the class IIa scaffold TMP269 as a starting point, researchers designed and synthesized a new series of HDAC4/7-targeted inhibitors.
• Structure-guided optimization of the metal-proximal and hydrophobic-binding regions yielded analogs with improved potency and greater isoform selectivity.
• Luciferase transcriptional assays, protein-binding studies, and docking analyses revealed distinct SAR patterns that separately govern selectivity for HDAC4 versus HDAC7.
• The resulting compounds offer selective chemical probes for dissecting HDAC4 and HDAC7 function in Th17 biology and a foundation for future therapies targeting Th17-driven inflammatory disease, including IBD.

Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription ↗

• "Scope" describes a mid-sized (10k-50k compound) chemical space positioned between minimal fragments and fully elaborated low-molecular-weight libraries, designed to maximize ligand efficiency and medicinal chemistry tractability.
• The authors introduce "Scope ring systems" (ring-X-ring) as a core organizing concept for building libraries and guiding functionalization toward sufficient potency.
• A 10k-compound Scope screening set — evaluated by SPR, native mass spectrometry, DSF, and biochemical assays — matches general diversity sets' primary hit rates even at higher screening concentrations, while showing superior ligand efficiency and higher hit rates after counter-screening.
• Case studies on trypanosomal CLK1 kinase, a 14-3-3/estrogen receptor-alpha molecular glue project, and SARS-CoV-2 main protease show the set yields diverse, tractable, ligand-efficient hits across varied binding sites.

The Scope Concept: Defined Chemical Space for Identifying Ligand-Efficient, Tractable Hits Applied to Drug Discovery Targets Trypanosomal CLK1, 14–3–3/Estrogen Receptor-α, and SARS-CoV-2 Mpro ↗

• Aromatase (CYP19A1) catalyzes the final step converting androgens to estrogens, and its activity drives tumor proliferation in estrogen receptor-positive (ER+) breast cancer, making it a long-validated target for hormonal therapy.
• Existing steroidal and nonsteroidal aromatase inhibitors (AIs) are effective as first-line treatments but face limitations from acquired resistance and off-target/tolerability issues, motivating a search for new chemical starting points.
• Researchers applied bioisosteric replacement strategies to a flavonoid-derived scaffold, a plant-derived chemotype structurally distinct from current AI drug classes, to generate a series of novel candidate inhibitors.
• The substitutions were assessed computationally for how they might alter predicted binding within the CYP19A1 active site, alongside their effects on physicochemical and ADME-relevant properties.
• The overall goal is a lead series that suppresses estradiol biosynthesis while addressing some of the structural liabilities associated with existing AI chemotypes.

Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer ↗

• A new benchmarking study examines a virtual-screening pipeline that chains structure-based co-folding models with learned-affinity scoring, an increasingly common setup for computational hit-finding.
• The cascade was applied to the Keap1-Nrf2 protein-protein interaction, a notoriously hard-to-drug target due to its flat, polar interface.
• Instead of trusting only the final ranked output, the authors assessed each stage separately against experimentally meaningful signal.
• They identify specific points where a stage's score diverges from that signal, a failure mode that can mislead downstream compound prioritization.
• The paper proposes per-stage control checks practitioners can run before relying on a cascade's final hit list, framing the work as a methodology and reliability study rather than a report of a new inhibitor.

Per-Stage Controls and Failure Modes in a Co-Folding Virtual Screening Cascade for the Keap1–Nrf2 Interaction ↗

• TAAR1 is a G protein-coupled receptor pursued as a non-dopaminergic drug target for schizophrenia and antipsychotic therapy.
• A structure-based virtual screen docked about 65 million candidate molecules against an active-state model of TAAR1.
• Of 55 top-ranked hits tested experimentally, 14 showed genuine TAAR1 agonist activity, ranging from mid-nanomolar to micromolar potency.
• Hit optimization then yielded agonists with nanomolar potency, and cryo-EM structures confirmed the binding poses the docking had predicted.
• Three optimized agonists showed high brain exposure and potency described as exceeding that of ulotaront, a clinical-stage TAAR1 antipsychotic candidate.
• In mice, all three normalized amphetamine-induced disruption of pre-pulse inhibition, a schizophrenia-relevant behavioral measure, without causing catalepsy, a common antipsychotic side effect.

Structure based discovery of antipsychotic-like TAAR1 agonists ↗

• RIBOTACs (ribonuclease-targeting chimeras) are heterobifunctional small molecules that recruit an endogenous ribonuclease to degrade a chosen RNA, rather than inhibiting a protein directly.
• This study applies the approach to cMYC mRNA; cMYC is an oncogenic transcription factor long considered "undruggable" because no direct small-molecule inhibitors have reached clinical use.
• Researchers systematically varied the length and rigidity of the linker connecting the RNA-binding ligand to the ribonuclease-recruiting moiety.
• Linker geometry proved to be a key determinant of how efficiently the RIBOTAC promotes cMYC mRNA degradation.
• Optimized linkers translated into improved downstream modulation of cMYC protein levels in cell-based assays.
• The findings support linker engineering as a general design lever for RIBOTAC-based RNA-targeted therapeutics.

Linker Optimization of cMYC RIBOTAC for Efficient cMYC Modulation ↗

• CYP8B1 is a liver enzyme in the bile-acid synthesis pathway now being explored as a drug target for metabolic disorders such as nonalcoholic fatty liver disease and type 2 diabetes.
• The project started from compound 1, a CYP8B1 inhibitor identified by high-throughput screening, which broke down too quickly to be tested in live animals.
• Chemists used structure-based design and metabolite identification to learn how the molecule degraded, then ran DMPK-guided analog synthesis to explore structure-activity relationships.
• That work produced compound 9, a quinoline analog with markedly improved metabolic stability.
• In mice, compound 9 showed robust in vivo CYP8B1 inhibition, providing a validated lead for further optimization.

Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease ↗

• HDAC4 and HDAC7 are class IIa histone deacetylases with limited tissue expression, making them attractive, more selective epigenetic drug targets than broadly expressed HDAC family members.
• Both enzymes help drive the transcriptional program behind Th17 cell differentiation, a pathway linked to inflammatory bowel disease and other Th17-associated inflammatory conditions.
• Chemists reworked the metal-binding and hydrophobic contact regions of TMP269, a known class IIa scaffold, to build a new series of HDAC4/7-directed analogs.
• Reporter-gene, binding, and docking studies uncovered distinct structural features that separately steer potency toward HDAC4 versus HDAC7.
• The work delivered isoform-selective, potent compounds usable as chemical probes to separately study HDAC4 and HDAC7 function, and as starting points for Th17-targeted therapeutics.

Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription ↗

• Researchers built STELLAR, a new docking workflow aimed at a persistent problem: current tools poorly handle long, highly flexible biopolymer ligands, including peptides exceeding roughly ten subunits, because of their vast conformational freedom.
• STELLAR splits such ligands into smaller fragments, docks each one separately, then reassembles them into a full-length, physically realistic pose, using established software including GNINA, RDKit, and GROMACS for refinement.
• Tested against known peptide-protein complexes from the Propedia database and the Protein Data Bank, the workflow reproduced experimentally observed binding poses with high accuracy.
• Compared with other state-of-the-art docking tools, it runs mainly on CPUs, scales linearly with ligand length, executes faster, and includes a ranking metric suited to high-throughput screening of long-chain polymer-protein interactions.

STELLAR: A Fragment-Based Docking Workflow for Highly Flexible Long-Chain Biopolymers ↗

• Researchers led by Seidler and colleagues designed a small-molecule inhibitor of p38δ (p38 delta), a MAP kinase linked to cancer, and reported its binding mechanism in Angewandte Chemie International Edition.
• Structural analysis showed the inhibitor initially collided with a flexible loop lining the kinase's ATP-binding pocket, a clash that would normally be expected to weaken or block binding.
• Instead of being excluded, the inhibitor caused that loop to change conformation and fold around the molecule, producing an unusually tight, self-encapsulating fit within the remodeled pocket.
• The authors present this induced-fit, pocket-remodeling behavior as a previously undescribed route to kinase selectivity, distinct from conventional structure-based design, which treats the binding pocket as a fixed template the inhibitor must be shaped to match.
• The finding suggests that deliberately exploiting pocket flexibility, rather than avoiding steric clashes, could become a strategy for engineering selectivity in future kinase-targeted drug design.

Thinking Outside the Binding Site: A Self‐Encapsulating Kinase Inhibitor Remodels Its Pocket to Achieve Selectivity ↗

• Researchers applied dynamic combinatorial chemistry (DCC), a hit-finding method in which reversible chemical building blocks assemble and reassemble under target guidance, letting the biological target itself select its best-binding partners.
• A new platform uses short peptide nucleic acid (PNA) tags to template three-fragment combinations, generating a library of 125,000 possible trivalent assemblies screened against thrombin.
• Candidate complexes are isolated by size-exclusion filtration and identified by MALDI mass spectrometry, compressing an entire selection-and-readout cycle to under an hour.
• Thrombin favored combinations engaging its active site and both flanking exosites at once, and this trivalent binding mode underlies the exceptionally tight affinity.
• The winning assembly is a fully reversible inhibitor with sub-picomolar affinity, achieving near-stoichiometric inhibition of thrombin activity.

Discovery of a Reversible Sub‐Picomolar Thrombin Inhibitor Using DCC ↗

• TRIM24 is a dual-module epigenetic "reader" whose bromodomain binds acetylated histones and is an established cancer drug-discovery target, though its nonhistone binding partners have been poorly defined.
• Researchers installed genetically encoded photocrosslinkers, AzF and BzF, at residue L922 within the bromodomain's acetyllysine pocket, preserving histone binding while enabling UV-triggered covalent capture of interacting proteins.
• Quantitative proteomics identified the nonhistone proteins NPM1 (AzF-enriched) and CDK9 (BzF-enriched), plus candidates MAP4, RAN, and SND1.
• ChIP-seq showed TRIM24, CDK9, and NPM1 co-localize near transcription start sites of cancer-associated genes; KEGG analysis tied the hits to several signaling pathways.
• The approach shows photocrosslinking can extend reader-domain interactome mapping beyond histones, yielding new candidate leads for chemical-probe and target-discovery work on TRIM24.

Mapping the Nonhistone Interactome of the TRIM24 Bromodomain Using Genetically Encoded Complementary Photocrosslinkers ↗

• Cryo-EM structures of the CTLH-MKLN1 E3 ligase, bound to three distinct substrate proteins, map how this receptor engages its targets.
• MKLN1 uses its discoidin and Kelch domains together, contacting substrates at multiple points rather than one binding surface.
• MKLN1 recognizes copies of itself via discoidin-Kelch pairing between dimers, competing with binding of other substrates.
• For ZMYND19 and adaptor-bound UNG2, C-terminal arginine residues insert into MKLN1's Kelch channel, marking MKLN1 as an arginine/C-degron receptor.
• A separate adaptor positions UNG2's acetylated N-terminus in an internal tunnel, revealing a distinct acetyl-N-terminal degron pathway.
• The findings broaden known E3 ligase substrate-recognition mechanisms, relevant to targeted protein degradation strategies beyond CRBN and VHL.

Multimodal substrate recruitment enables CTLH-MKLN1 E3 ligase to target N-, C-, and internal degrons ↗

• BmTACs — a new class of brain-penetrant degrader molecules — fuse a macrocyclic peptide shuttle to a PROTAC-type small-molecule module.
• The peptide shuttle exploits a transcytosis route across brain blood vessels that becomes more active with age, enabling efficient blood-brain-barrier crossing and neuronal delivery.
• A chemical cage on the degrader's VHL-recruiting ligand keeps it silent until it meets the high-oxidative-stress conditions found in Alzheimer's-affected tissue, limiting activity elsewhere in the brain.
• Once activated, the compound selectively degrades an activated, disease-linked form of the kinase DAPK1.
• In aged Alzheimer's-model mice, systemic treatment reduced activated DAPK1, lessened amyloid-beta and tau pathology, and improved cognitive function, demonstrating an aging-adapted strategy for brain-targeted protein degradation.

Blood-Brain Barrier-Permeable Macrocyclic Chimeras (BmTACs) for Targeted Protein Degradation in the Aging Brain ↗

• CASP4, an inflammatory caspase linked to Alzheimer's disease, is the target of a new computational drug-repositioning pipeline built to screen DrugBank compounds for potential inhibitors.
• The workflow combined docking-based prioritization with ChemBERTa language-model embeddings and physicochemical descriptors to train machine-learning classifiers.
• A Random Forest classifier and regressor were used to identify likely active compounds and rank them by predicted potency.
• Downstream cheminformatics, PK-PD evaluation, and molecular docking narrowed the pool to five repositioning candidates.
• Molecular dynamics simulations and MM/PBSA free-energy analysis were then applied to assess binding stability, identifying two compounds (DB05316 and DB00519) with predicted binding compared favorably to the reference drug donepezil.
• The authors present the pipeline as a general strategy for prioritizing repurposed compounds against novel drug targets.

AI Accelerated Chemical Screening Integrates ChemBERTa to Identify Repositionable CASP4 Inhibitors via MD Simulations and MM/PBSA Analysis ↗

• Oligonucleotide backbone chemistry gets a new modular entry point: an H-phosphonate diester dinucleotide 'blockmer' platform that builds backbone-modified oligonucleotides through standard solid-phase synthesis.
• The method exploits the ambiphilic reactivity of H-phosphonate diesters, allowing diverse phosphate backbone modifications to be installed without air- or moisture-sensitive P(III) reagents or hazardous chemicals.
• Accessible backbone modifications span a wide range, from simple alkyl substitutions to sulfonamide-linked phosphate analogs, well beyond conventional phosphorothioate-type chemistries.
• Because the dinucleotide blockmers are compatible with existing solid-phase assembly workflows, they can be combined and positioned flexibly within a single oligonucleotide sequence.
• The platform is designed to enable systematic backbone structure-activity relationship studies in oligonucleotide drug discovery, providing a scalable and robust route for rapid analog generation.

Versatile H-Phosphonate Platform for Backbone-Modified Dinucleotide Blockmers Enabling Oligonucleotide SAR ↗

• A programmable, bifunctional pyridine scaffold bearing a thianthrenium leaving group and a fluorine handle enables two sequential, chemoselective coupling reactions — first with alkylamines, then with cysteine thiols.
• The resulting aryl-cysteine linkage is non-chiral and stable, addressing limitations of existing bioconjugation approaches that often yield reversible linkages or stereochemical mixtures.
• Both coupling steps show high functional-group tolerance and chemoselectivity, making the chemistry compatible with complex peptides and proteins.
• The platform was applied to late-stage peptide diversification and stapling, as well as site-selective protein functionalization.
• Researchers also used the method to build an analog of the HER2-targeting antibody-drug conjugate MRG002 with a tunable drug-to-antibody ratio, reporting improved payload retention in serum relative to conventional linkage chemistry.

Modular Assembly of Bioconjugates Enabled by a Pyridine-Based Chemoselective Sequential Conjugation Platform ↗

• Ligands that bind deubiquitinating enzymes (DUBs) without blocking their catalytic activity are notoriously hard to find — a new on-bead, proximity-driven functional screening platform is designed to identify them.
• Such noninhibitory DUB ligands are essential for building DUBTACs (deubiquitinase-targeting chimeras), bifunctional molecules that stabilize target proteins by recruiting DUBs to strip ubiquitin marks, the inverse of degrader-based targeted protein degradation.
• That rarity has made noninhibitory DUB ligands the central bottleneck in DUBTAC development.
• Using the platform, the team discovered a previously unreported noninhibitory ligand for the deubiquitinase USP7.
• Conjugating this USP7 ligand to a CFTR-binding moiety produced a DUBTAC lead, WJ045, which stabilized cellular CFTR protein levels.
• The results demonstrate the platform's utility for discovering DUB-recruiting ligands and advancing targeted protein stabilization, with relevance to cystic fibrosis biology.

A Proximity-Driven Functional Screening Platform for the Discovery of Noninhibitory USP7 Ligand Enabling Targeted Protein Stabilization ↗

• WBP4, a spliceosome-associated scaffold protein long considered undruggable, now has a first-in-class molecular glue degrader: dWBP4-1, which selectively eliminates it.
• The compound works through the CRBN E3 ligase, engaging WBP4 via a canonical G-loop interface to trigger rapid, highly potent degradation.
• Proteome-wide profiling showed the degrader was highly selective, with minimal off-target effects on gene expression or splicing patterns.
• The team pinpointed a compact 41-amino-acid region of WBP4 sufficient to serve as a degradation tag, naming the resulting chemical-genetic system "wTAG."
• When attached to other proteins of interest, wTAG enabled clean, dose-dependent degradation without the "hook effect" that limits many degrader tools, expanding its potential as a general research platform.

Selective and Potent First-in-Class CRBN-Dependent Molecular Glue Degraders of WW Domain-Binding Protein 4 ↗

• PA-HDCI, a near-infrared fluorogenic probe built on the HDCI fluorophore scaffold, localizes to the endoplasmic reticulum and reports on human carboxylesterase 2A (hCES2A) activity in living cells and animals.
• The probe combines a large Stokes shift, high metabolic stability, and reliable ER targeting, enabling in situ, real-time imaging of hCES2A function across multiple biological systems.
• Using PA-HDCI in a high-throughput screening assay, the team identified compound A4, a highly potent covalent inhibitor of hCES2A.
• hCES2A is the intestinal enzyme that converts the chemotherapy drug irinotecan into its toxic active metabolite, driving irinotecan-induced intestinal toxicity (IIT).
• In tumor-bearing mouse models, A4 showed a favorable safety profile and reduced irinotecan-associated intestinal toxicity while therapeutic efficacy was maintained.
• Together, the work delivers both a new imaging tool and a validated drug-discovery platform for hCES2A-targeted therapeutics.

An ER-Targeting Near-Infrared Fluorogenic Probe for In Situ hCES2A Functional Imaging and Inhibitor Discovery ↗

• Ligand-based virtual screening pipeline mined DrugBank for CASP4 inhibitor candidates, combining docking-score prioritization with SMILES-derived ChemBERTa embeddings and physicochemical descriptors.
• A Random Forest classifier trained on the hybrid ChemBERTa/physicochemical feature set separated active from inactive compounds with high accuracy and enriched actives among top-ranked hits.
• A companion Random Forest regressor, trained on experimental pIC50 values, ranked candidates by predicted potency.
• Cheminformatics filtering, PK-PD evaluation, and molecular docking narrowed the field to five DrugBank-listed candidates.
• Molecular dynamics simulations and MM/PBSA free-energy analysis confirmed stable binding poses for the top candidates.
• Positions the workflow as a drug-repositioning route toward CASP4-targeted Alzheimer's disease therapy, a caspase linked to neuroinflammation and pyroptosis.

AI Accelerated Chemical Screening Integrates ChemBERTa to Identify Repositionable CASP4 Inhibitors via MD Simulations and MM/PBSA Analysis ↗

• Discovered dWBP4-1 through proteomic profiling of a CRBN-binding compound library, followed by SAR optimization.
• Acts as a molecular glue, forming a CRBN ternary complex via a canonical G-loop-mediated interaction to recruit WBP4 (WW domain-binding protein 4), a spliceosome-associated scaffold protein.
• Degradation is rapid and occurs at nanomolar concentrations.
• Selectivity across the proteome is reported as high, with minimal downstream transcriptomic or alternative-splicing effects observed elsewhere.
• Mapped a minimal ~41-residue WBP4 degron sequence and used it to build "wTAG," a fusion-tag degradation platform.
• wTAG enables monotonic, dose-dependent degradation without the hook effect seen in some bifunctional degraders.

Selective and Potent First-in-Class CRBN-Dependent Molecular Glue Degraders of WW Domain-Binding Protein 4 ↗

• Custom bifunctional amino acids — carrying a VHL-recruiting ligand and a variable linker — are incorporated directly during solid-phase peptide synthesis, an alternative to conventional PEG-based linkers for building cyclic peptide degraders.
• A SICLOPPS-derived cyclic peptide HIF-1 inhibitor serves as the warhead, yielding cyclic peptide PROTACs (CP-PROTACs) that engage VHL in a productive ternary complex.
• The degraders lower HIF-1α levels and hypoxia-response signaling across multiple cancer cell lines.
• Degradation is oxygen-state dependent — robust under moderate hypoxia but largely lost under more severe hypoxia, even though the degrader still engages and marks HIF-1α there.
• The activity loss reflects a kinetic mismatch, not a binding failure: HIF-1α resynthesis outpaces degradation, pointing to a general ceiling on PROTAC efficacy against rapidly replenished targets.

Cyclic Peptide PROTACs Restore VHL-Mediated HIF-1α Degradation in Hypoxia ↗

• GPR41/FFAR3, a short-chain-fatty-acid-sensing GPCR, was tested as a target for dampening gut-derived endotoxemia in a macrophage model of endotoxin stress.
• The selective agonist AR420626 activated GPR41 and blunted downstream pro-inflammatory signaling, cutting output of nitric oxide, IL-6, MCP-1, and iNOS.
• This anti-inflammatory effect tracked to suppression of NF-κB signaling, the central pathway driving those mediators.
• Agonist treatment also boosted autophagic flux, marked by increased LC3-I-to-LC3-II conversion.
• Blocking autophagy pharmacologically erased AR420626's protective effect, indicating autophagy induction is mechanistically required rather than incidental to the anti-inflammatory action.
• Findings position GPR41 as a druggable node linking gut microbial metabolite sensing to control of systemic inflammation in metabolic endotoxemia.

G-Protein-Coupled Receptor 41 (GPR41) as a Therapeutic Target for Metabolic Endotoxemia: Mechanistic Insights into AR420626-Induced Autophagy and Nuclear Factor kappa B (NF-κB) Suppression ↗

• Combined protein–ligand docking, ML force fields, quantum chemistry, and free-energy perturbation (FEP) to screen roughly 5 million hypothetical photoactive PARP1 ligands.
• Docking identified candidates with differential PARP1 binding between light-exposed and dark states; ML force fields and QM calculations predicted pKa, absorption spectra, and thermal half-lives, while graph-based surrogate models screened the remaining library.
• Excited-state nonadiabatic dynamics simulations (with ML force fields) estimated photoswitching quantum yields; FEP refined binding-affinity predictions for top hits.
• Prioritized a small set of synthetically accessible candidates combining red-shifted absorption (favoring deeper tissue penetration), therapeutically suitable thermal half-lives, and light/dark-selective PARP1 binding.
• Predictions were experimentally validated, demonstrating an end-to-end computational-to-experimental pipeline for designing light-activated (photopharmacological) cancer therapeutics.

Computational Design and Experimental Validation of Photoactive PARP1 Inhibitors ↗

• Introduces reactive metallo-scaffolds (r-mS), a new class of covalent metal complexes bearing a chloroacetamide electrophile designed to engage ligandable cysteines across the proteome.
• Chemoproteomic profiling of a focused r-mS series in HEK293T cell lysate mapped novel cysteine engagement proteome-wide.
• Metal identity, arene substituents, and overall scaffold topography together tune cysteine reactivity and targeting selectivity.
• Lead compound r-mS-2 engages a cysteine within the functionally relevant SAM-binding domain of the methyltransferase PRMT1, confirmed by intact-protein LC-MS.
• That engagement functionally inhibits PRMT1 activity, tying a covalent hit directly to modulation of a validated target.
• Positions the platform as a generalizable route to target discovery for rational, next-generation metallodrug design.

Proteome-Wide Target Identification Using Reactive Metallo-Scaffolds (r-mS): A Platform for Metallodrug Discovery ↗

• A PNA-templated dynamic combinatorial chemistry (DCC) platform assembles a three-fragment library (~125,000 possible combinations) using DNA/PNA hybridization handles for unbiased equilibration.
• Thrombin itself templates the library, selecting and amplifying the best-binding fragment combination; size-exclusion filtration coupled with MALDI mass spectrometry gives a full selection-to-readout cycle in under an hour.
• The selected trivalent assembly engages thrombin's active site plus both exosites simultaneously, driving exceptionally high (sub-picomolar-range) binding affinity and near-stoichiometric inhibition.
• Unlike covalent thrombin inhibitors, binding is fully reversible — pharmacologically relevant for an anticoagulant, where reversibility matters for managing bleeding risk.
• Demonstrates target-templated DCC as a rapid route to multivalent, exosite-spanning inhibitors, even against a well-studied target.

Discovery of a Reversible Sub-Picomolar Thrombin Inhibitor Using DCC ↗

• Genetic code expansion installed site-specific photocrosslinkers (AzF and BzF) at residue L922, within the acetyllysine-binding pocket of the TRIM24 bromodomain.
• Both crosslinker variants retained recognition of acetylated histones and crosslinked efficiently under UV, enabling interaction-based protein profiling (IBPP) in a native context.
• Quantitative proteomics of the two complementary probes gave differing capture profiles: AzF enriched for NPM1, BzF enriched for CDK9, with MAP4, RAN, and SND1 as additional candidates.
• ChIP-seq showed TRIM24, CDK9, and NPM1 co-occupying regions near transcription start sites of cancer-associated genes.
• Together the results suggest the TRIM24 bromodomain reads acetylation on nonhistone proteins as well as histones, broadening its reader function and informing chemical-probe design against this pocket.

Mapping the Nonhistone Interactome of the TRIM24 Bromodomain Using Genetically Encoded Complementary Photocrosslinkers ↗

• Researchers screened a library of 1,280 known bioactive compounds in search of pharmacological activators of the mitochondrial calcium uniporter complex (MCUc), a target for which potent, selective agonists have been scarce.
• The screen identified CGP7930 — a compound previously characterized as a GABA-B receptor allosteric modulator — as a potent activator of mitochondrial calcium uptake, highlighting a drug-repurposing angle for a difficult target.
• Mechanistic follow-up showed the activating effect depends on MICU1, a key regulatory subunit of the uniporter complex, pointing to a specific mode of action rather than a nonspecific membrane effect.
• Enhanced mitochondrial calcium entry translated into improved cardiac contractile bioenergetics, suggesting relevance to conditions involving impaired heart energy metabolism.
• The work provides a valuable pharmacological tool compound and a starting point for developing more selective next-generation MCU activators.

High-throughput screen identifies a potent MCU activator boosting cardiac contractile bioenergetics ↗

• AKR1B10 is an aldo-keto reductase enzyme overexpressed in several cancer types, making it an attractive but challenging drug target.
• Researchers used Boltz-2, an AI-based protein-ligand co-folding model, to computationally screen a large, chemically diverse compound library and prioritize a small, diverse shortlist of candidates for lab testing.
• Experimental testing of that shortlist produced an unusually high hit rate, with most of the tested compounds showing real inhibitory activity against AKR1B10.
• Several confirmed hits reached submicromolar potency and carried chemical scaffolds not previously reported as AKR1B10 inhibitors.
• The results support co-folding AI models as a practical, resource-efficient way to convert computational predictions into experimentally validated drug leads, reducing reliance on brute-force screening.

Efficient Discovery of Potent AKR1B10 Inhibitors Using Co-folding Model Boltz-2 ↗

• Camptothecin-class payloads such as DXd currently dominate antibody-drug conjugate (ADC) design, powering approved drugs in the Enhertu family.
• Researchers created a new homocamptothecin analog, H2, built around a simplified seven-membered-ring (hydroxybutyl) core that avoids the lengthy, multi-step F-ring synthesis required for DXd-type payloads.
• H2 retained potent intrinsic cytotoxicity while showing markedly better resistance to hydrolytic breakdown than earlier homocamptothecin designs.
• Trastuzumab-based ADC candidates carrying H2 produced strong bystander-killing effects and antiproliferative activity in vitro, mirroring T-DXd.
• In a HER2-positive xenograft tumor model, the H2-based conjugates matched the antitumor efficacy of the benchmark payload T-DXd.
• The results position the simplified homocamptothecin scaffold as a promising, more synthetically accessible class of next-generation ADC payloads.

Homocamptothecin Payloads with Enhanced Potency for Antibody-Drug Conjugates ↗

• VAV1 is a hematopoietic-restricted signaling protein of interest in blood cancers and autoimmune conditions, prompting efforts to target it via induced protein degradation.
• High-throughput, unbiased global proteomics screening identified phenyl-glutarimide degrader compounds that recruit CRBN to selectively degrade VAV1.
• VAV1's C-terminal SH3-2 domain proved essential for ternary complex formation, and structural work uncovered a novel "RT-loop" degron there—distinct from the "G-loop" degrons used by other CRBN glues—validated by mutagenesis.
• An AI-based protein structure-prediction workflow modeled the ternary complex to support this mechanistic finding.
• Free energy perturbation calculations on the predicted structures generated cooperativity scores that correlated with experimental potency, demonstrating a computational strategy to prioritize and optimize molecular glue analogs faster than empirical screening alone.

Leveraging high-throughput proteomics and AI-based protein folding to accelerate VAV1 molecular glue discovery ↗

• B3GAT3 (beta-1,3-glucuronosyltransferase) is overexpressed in hepatocellular carcinoma (HCC) and correlates with poor patient prognosis, marking it as a promising but previously untargeted anti-cancer target.
• The research team started from TMLB-C16, an in-house lead compound with micromolar-range inhibitory potency against B3GAT3.
• Using structure-guided design, they synthesized 60 novel derivatives built on a 6-methoxyquinoline-4-carboxamide scaffold, systematically probing structure-activity relationships (SAR).
• This optimization campaign identified TMLB-G9, a candidate whose potency improved dramatically, moving from the micromolar starting point to nanomolar activity.
• TMLB-G9 is reported as a first-in-class B3GAT3 inhibitor, offering a new chemical starting point for potential HCC drug development.

Structure-Guided Design, Synthesis, and Evaluation of Novel 6-Methoxyquinoline-4-carboxamide Derivatives as First-in-Class Nano-Molar B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma ↗

• Starting from JK-4b, a potent but overly cytotoxic non-nucleoside reverse transcriptase inhibitor (NNRTI), researchers pursued structure-guided optimization to fix its safety liability.
• Design efforts targeted the NNRTI entrance channel, a sub-pocket near the classical allosteric site, to reshape how analogs bind reverse transcriptase and reduce off-target toxicity.
• Structure-activity relationship (SAR) studies across this new series pointed to compound 9n as the standout, with markedly improved selectivity and much lower cytotoxicity than JK-4b.
• Despite the safety redesign, 9n kept potent antiviral activity against both wild-type HIV-1 and clinically relevant drug-resistant variants, preserving the lead's core strength.
• The work illustrates entrance-channel-focused chemistry as a practical strategy for detoxifying promising but toxicity-limited NNRTI candidates.

Targeting the HIV-1 NNRTI Entrance Channel: Structure-Guided Optimization for Enhanced Safety and Selectivity ↗

• This J. Med. Chem. perspective synthesizes lessons from four clinical-stage oral, nonpeptidic GLP-1 receptor agonists—danuglipron, lotiglipron, DA-302168S, and orforglipron—to outline a design blueprint for next-generation candidates.
• It frames a broader modality shift in metabolic disease therapeutics: from injectable peptide GLP-1RAs toward oral small molecules that could improve dosing convenience and patient acceptance.
• Orforglipron is highlighted as the first oral small-molecule GLP-1RA to reach approval, marking a proof-of-concept milestone for the class.
• The authors distill recurring structure-activity relationship tradeoffs among these first-generation candidates—balancing receptor potency, tolerability, and oral bioavailability—that shaped each program's clinical trajectory.
• Based on these comparisons, the review proposes design principles intended to guide future medicinal chemistry efforts toward improved oral GLP-1RAs.

Oral Small-Molecule GLP-1 Receptor Agonists: Lessons from Clinical Candidates and a Blueprint for Next-Generation Design ↗

• This is a perspective/analysis article, not a new experimental study, focused on Plasmodium falciparum apical membrane antigen 1 (PfAMA1) as an anti-malarial drug target.
• PfAMA1 binds rhoptry neck protein 2 (PfRON2) to form the moving junction that enables the malaria parasite to invade red blood cells, making this protein-protein interaction a key therapeutic target.
• Most structure-based inhibitor design has targeted the hydrophobic trough, a well-defined groove on PfAMA1 that accommodates the PfRON2 peptide.
• The authors highlight a domain 2 (D2) loop near the trough that shows cryptic, conformation-dependent dynamics rather than a fixed structure.
• They argue this loop flexibility, previously overlooked, meaningfully shapes how PfAMA1 recognizes PfRON2.
• The perspective calls for future anti-malarial drug design to incorporate D2 loop dynamics alongside the trough itself, rather than treating the binding site as static.

Beyond the Hydrophobic Trough of PfAMA1: Pivotal Roles of Cryptic Loop Dynamics Inform Anti-Malarial Therapeutic Design ↗

• DNA-encoded libraries (DELs) let researchers screen ultralarge collections of macrocyclic peptides to find hit compounds for drug discovery, but efficient on-DNA cyclization chemistry has remained a bottleneck.
• A new on-DNA macrocyclization method uses sulfur(VI) fluoride exchange (SuFEx), a fast, click-type reaction, to close peptide rings directly on DNA tags.
• The design embeds a phenol and an aryl sulfonyl fluoride within a single DNA-tagged peptide, positioning the two groups to react with each other intramolecularly.
• Simply dissolving the construct in basic aqueous buffer triggers rapid, high-conversion cyclization without added catalysts or harsh conditions.
• The method enables efficient, high-yielding synthesis of ultralarge DNA-encoded macrocyclic peptide libraries, expanding the chemical space available for DEL-based hit discovery.

SuFEx Cyclization Enables DNA-Encoded Macrocyclic Peptide Libraries for Drug Discovery ↗

• CD38 is an enzyme central to NAD+ metabolism and calcium signaling in cells, and interest has grown in targeting it for neurological and psychiatric conditions.
• The authors designed a new tricyclic chemical series that binds CD38 by forming an adduct with the ADPR co-substrate, inhibiting the enzyme through an uncompetitive mechanism.
• Locking the molecules into their active shape — achieved by covalently linking a six-membered heteroaromatic core to an imidazole warhead — boosted biochemical activity against both mouse and human CD38.
• Iterative tuning of the core and linker chemistry, guided by physicochemical properties, improved how much unbound compound reached the brain relative to plasma in mice.
• The resulting lead, compound 16, raised NAD+ levels in mouse brain and lung tissue in a dose-dependent manner across an oral dosing range tested in vivo.

Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors ↗

• Antimicrobial resistance is narrowing treatment options for pathogens like Staphylococcus aureus and Neisseria gonorrhoeae, motivating new computational discovery tools.
• MAPViS, a multimodal deep-learning framework, fuses molecular graph, fingerprint, and descriptor/3D geometric features via gated fusion, pretrained on ~10 million molecules using hierarchical pseudolabel classification and masked graph contrastive learning.
• After fine-tuning, it jointly predicts antibacterial activity against S. aureus and N. gonorrhoeae plus cytotoxicity risk in three human cell lines (HepG2, HSkMC, IMR-90).
• On benchmark and external validation data, MAPViS showed strong early-enrichment performance for S. aureus, with all ten top-ranked candidates confirmed experimentally active, while generalization to N. gonorrhoeae was more modest.
• The authors describe MAPViS as a scalable tool for joint activity-toxicity modeling to support antibiotic virtual screening.

A Task-Adaptive Multimodal Pretrained Framework for Antibiotic Virtual Screening with Joint Activity and Cytotoxicity Prediction ↗

• NatA catalyzes a large share of eukaryotic Nα-acetylation, a co-translational modification important for protein stability, localization and function; no validated small-molecule NatA probe had previously been reported.
• Screening an in-house ~700-compound library and optimizing a thiadiazolidinedione scaffold identified tideglusib (YD3139) — a clinical-stage GSK-3β inhibitor — as a hit, repurposing a known drug toward NatA.
• Mechanistic studies showed tideglusib first binds NatA allosterically, after which CoA released during catalysis chemically modifies it into a reversible covalent adduct, a previously undescribed catalysis-dependent inhibition mechanism.
• The compound showed low-micromolar potency against yeast and human NatA with good selectivity over other NAT family members, and proteomics confirmed on-target activity in yeast cells, validating it as a mechanistic chemical probe.

Tideglusib as a First-in-Class Chemical Probe for NatA: Identification, Mechanism, and Cellular Validation of an Allosteric, CoA-Dependent Inhibitor ↗

• Researchers combined XChem crystallographic fragment screening with in silico screening, then merged fragment hits into covalent leads targeting the Kalirin-Rac1 GEF-GTPase complex.
• Instead of directly competing with GTP/GDP for Rac1's binding site, the covalent compounds act as molecular glues, locking Kalirin and Rac1 into an inactive ternary complex that blocks nucleotide exchange.
• Two resulting inhibitors, RS-009 and MC-278, reduce Kalirin's GEF activity through this dual action: partial nucleotide competition plus stabilization of the non-productive complex.
• Biochemical selectivity panels and cellular activity-based protein profiling show the compounds can distinguish among different GEF-GTPase pairs rather than acting indiscriminately.
• The authors frame this as an alternative to direct GTPase inhibition that could offer finer spatiotemporal control, positioning RS-009/MC-278 as chemical probe candidates.

Discovery of a molecular glue inhibitor that stabilises a non-productive Kalirin-Rac1 complex ↗

• Virtual screening often yields false positives from fast, approximate scoring functions, while accurate free-energy calculations to filter them remain too costly for routine high-throughput use.
• The authors introduce CTMD (c(t)-based metadynamics), which ranks binding stability using the nonequilibrium reversible-work estimator c(t) from short, independent metadynamics runs, without requiring converged binding free energies.
• Across diverse targets and chemotypes, CTMD shows robust early enrichment while staying fast, transferable, and largely tuning-free.
• Benchmarking AI co-folding, the authors find Boltz-2's enrichment tracks similarity to its training data and persists even after active-site modifications, pointing to memorization rather than true binding physics.
• CTMD is offered as an open-source middle ground between quick docking/co-folding and costly free-energy methods, cutting wasted discovery-campaign resources.

Early-Enrichment Hit Discovery via Reversible-Work c(t) Estimation in Metadynamics (CTMD) ↗

• Chemists conjugated the beta-lactam antibiotic aztreonam to aerobactin, a bacterial iron-scavenging siderophore, exploiting bacteria's own iron-uptake machinery as a 'Trojan horse' to smuggle the drug inside cells.
• A modular synthetic route enabled controlled mono- and di-functionalization of aerobactin, with late-stage click-chemistry (CuAAC) attachment of payloads, providing a flexible platform applicable beyond this single conjugate.
• The lead monovalent conjugate was markedly more potent than aztreonam alone against a hypervirulent, clinically concerning Klebsiella pneumoniae strain, a substantial improvement over the parent antibiotic.
• Competition and iron-dependent activity studies confirmed delivery proceeds through the aerobactin iron-acquisition pathway, supporting genuine siderophore-mediated uptake rather than incidental potency gains.
• The results establish aerobactin as a viable scaffold for delivering antibacterial payloads against multidrug-resistant, hypervirulent Enterobacteriaceae.

Modular Synthesis of Aerobactin–Aztreonam Conjugates with Enhanced Activity against Hypervirulent Klebsiella pneumoniae ↗

• Researchers used bicyclic genetically encoded peptide libraries (BiGEL) — phage-displayed peptides chemically stapled into two rings — to search for inhibitors of Siglec-7, a glycan-binding immune receptor considered notoriously hard to target with small molecules.
• Sequencing-based panning against Siglec-7 nominated hundreds of candidate peptides; a subset were confirmed as genuine binders by surface plasmon resonance and as functional disruptors of the Siglec-7:GD3 interaction by competitive ELISA, with machine learning models identifying further hits of similar potency.
• Structure-activity work showed the bicyclic ring architecture itself is essential for potency, and NMR studies located one optimized lead's binding site away from the canonical glycan-binding domain, pointing to a possible allosteric mechanism.
• Cell-based multivalent binding assays confirmed engagement with Siglec-7 but also revealed considerable nonspecific binding to receptor-negative cells, highlighting a selectivity challenge still to be resolved.

Noncarbohydrate Inhibitors of Sialic Acid-Binding Immunomodulatory-Type Lectin-7 (Siglec-7) Discovered from Genetically Encoded Bicyclic Peptide Libraries ↗

• TRI-611 is an orally dosed molecular glue degrader designed to eliminate ALK fusion proteins that drive a subset of non-small cell lung cancers.
• Rather than blocking ALK's active site like conventional inhibitors, it recruits the E3 ligase adaptor cereblon to a distinct surface on ALK, forming a complex that tags the protein for degradation.
• The molecule is reported to be highly selective, sparing other cereblon-dependent targets and unrelated kinases, and it degrades both wild-type and kinase-inhibitor-resistant ALK fusion variants.
• A central finding is brain penetrance: TRI-611 produced tumor regressions in intracranial as well as subcutaneous models, addressing CNS metastases that limit many existing ALK-targeted therapies.
• Degradation was rapid and long-lasting, and combining TRI-611 with standard ALK inhibitors produced more durable responses in preclinical models.

TRI-611, a selective, brain-penetrant molecular glue degrader of ALK ↗

• The preprint asks a foundational methods question: given the size of a typical structure-based virtual screening benchmark, how large a difference in AUROC or enrichment between two protocols can actually be distinguished from statistical noise.
• Rather than assuming benchmark comparisons are inherently reliable, the authors first directly measure these resolution limits.
• They then pre-registered six candidate interventions to docking/scoring protocols and tested each against the measured resolution limits, rather than reporting post-hoc 'wins.'
• The pre-registration design is meant to guard against selective reporting, a known issue where small, benchmark-specific gains get presented as general improvements.
• This is a methodology/rigor study, not a new-inhibitor or target-specific paper; it addresses how virtual screening improvements should be evaluated.
• Practical implication: many published claims of improved virtual screening performance may fall within the noise floor of typical benchmarks, so hit-finding teams should treat single-benchmark improvement claims cautiously.

What actually moves virtual screening performance: two measured resolution limits and six pre-registered interventions ↗

• The EP4 receptor (EP4R), a prostaglandin E2 receptor subtype, is a promising immuno-oncology target because its signaling dampens antitumor immunity and drives tumor-associated inflammation.
• A scaffold hopping strategy moved medicinal chemists away from earlier EP4R antagonist chemotypes to a novel chemical series with improved potency and pharmacokinetics.
• Structure-activity relationship (SAR) studies then guided lead optimization, balancing target potency, selectivity, and drug-like properties.
• This process yielded DT-9081, an orally bioavailable small-molecule EP4R antagonist combining potent receptor antagonism, favorable ADME properties, and a clean preclinical safety profile.
• In vitro and in vivo pharmacology data support DT-9081's ability to modulate tumor immunity, and the compound has already completed a Phase I monotherapy trial in patients with solid cancers.

Discovery of DT-9081, a Potent and Orally Bioavailable Small Molecule Antagonist of the EP4 Receptor for the Treatment of Solid Cancers ↗

• Rather than inhibiting or trapping the PARP1 enzyme like approved PARP inhibitors (PARPis), researchers targeted the PARP1 gene promoter itself to shut down PARP1 production at the transcriptional level, aiming to avoid the hematologic toxicity and resistance mechanisms associated with PARPi-mediated PARP1 trapping.
• The promoter region forms a non-canonical (3+1) hybrid G-quadruplex structure distinguished by an adenine bulge, a distinctive DNA fold not previously exploited as a drug target.
• Combining computational modeling with biophysical characterization, the team identified a small molecule that selectively engages this unusual G-quadruplex architecture.
• In multiple myeloma cells, the compound reduced PARP1 expression, disrupted downstream DNA repair signaling, and triggered DNA damage-associated apoptosis.
• Healthy blood cells were largely spared, pointing to a possible therapeutic window distinct from conventional PARP inhibitor toxicity profiles.

Hit It before It Starts: Targeting a (3 + 1) Hybrid Non-canonical G-Quadruplex to Silence PARP1 in Cancer ↗

• GRP78 (BiP/HSPA5) is a chaperone in the highly conserved HSP70 family, making isoform-selective inhibitors difficult to design.
• Using a Direct-to-Biology (D2B) strategy — synthesizing and screening compounds without intermediate purification — researchers identified compound 12 as a selective GRP78 inhibitor.
• Compound 12 binds the peptide-binding pocket in GRP78's substrate-binding domain and is selective for GRP78 over other tested HSP70 isoforms.
• It potently and selectively kills A549 lung cancer cells while showing minimal activity in other tested lung cancer cell lines.
• Cellular thermal shift assay (CETSA) confirmed cellular target engagement, and compound 12 modulates GRP78-linked unfolded protein response (UPR) stress signaling.
• The authors present compound 12 as a chemical probe for studying GRP78 biology and a starting point for GRP78-targeted therapeutics.

Development of Isoform-Selective GRP78 Inhibitors from a Direct-to-Biology Strategy ↗

• Researchers describe a "2-in-1" PROTAC design that merges the CRBN-recruiting ligand into the capping group of an HDAC8 warhead, rather than linking two separate ligands.
• This lets one structural motif engage both HDAC8 and the CRBN E3 ligase, unlike conventional heterobifunctional PROTACs, whose separate POI- and E3-binding units plus linker often yield large, poorly drug-like molecules.
• Relative to the team's earlier HDAC8 degrader YX862, the new compact degraders show improved selectivity, lower molecular weight, and better overall drug-like properties.
• The compounds also achieved effective HDAC8 degradation in vivo, indicating therapeutic potential beyond cell-based activity.
• The study proposes a broader design framework for building smaller, more efficient PROTACs by integrating target engagement and E3 ligase recruitment into a single motif.

A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗

• p53 is the tumor suppressor most frequently inactivated in cancer, and hotspot mutations such as R280K and R273H destabilize the folded DNA-binding domain, making mutant p53 reactivation a long-standing 'undruggable' target class.
• The study describes RVJB59, a small molecule from a tryptophanol-derived oxazoloisoindolinone series, designed to covalently engage mutant p53 protein rather than bind it only reversibly.
• Biophysical thermal-stability assays reported for this compound series show increased melting stability of mutant p53 DNA-binding domains, consistent with partial restoration of a more folded, wild-type-like conformation.
• Combining covalent engagement with thermostabilization supports a mutant-reactivation strategy aimed at restoring p53 tumor-suppressor function in cancers driven by the R280K and R273H mutations.

Covalent Targeting and Thermostabilization of Oncogenic R280K and R273H Mutants p53 by Small Molecule RVJB59 ↗

• Researchers introduce a binding-to-release (BTR) strategy that triggers drug-conjugate payload release directly upon target binding, rather than requiring receptor-mediated endocytosis.
• The approach uses a new bioconjugation reaction, phosphorus(V)-phenol exchange (PhoPEx) — inspired by SuFEx click chemistry — engineered so that chemistry within the binding pocket itself cleaves the drug free once the conjugate engages its target.
• Because only a minority of drug targets support efficient endocytosis, this binding-triggered release could extend conjugate-based therapies to otherwise poorly internalizing targets.
• The authors describe proof-of-concept work with a conjugate targeting fibroblast activation protein (FAP), evaluated from in vitro settings through patient-derived tissue specimens.

A binding-to-release strategy for targeted anticancer drug delivery ↗

• Researchers report that 5-tBu-thalidomide, a chemically modified thalidomide analog, acts as a molecular glue that recruits the CRBN E3 ligase to drive potent, selective breakdown of FIZ1, a zinc-finger transcription factor linked to FLT3 signaling.
• FIZ1 contains eleven zinc-finger domains, several of which carry the degron sequence normally required for thalidomide-class drugs to engage, yet the compound acts almost exclusively through a single finger, zinc finger 8.
• Computational modeling of the CRBN–drug–FIZ1 ternary complex reveals the contacts that favor this domain over the others, explaining the selectivity.
• The work offers a template for rationally designing thalidomide-based glues that target individual zinc fingers within otherwise 'undruggable' transcription factors.

5-tBu-Thalidomide Is a Selective Molecular Glue Degrader of the Transcription Factor FLT3 Interacting Zinc Finger 1 (FIZ1) ↗