Daily medicinal chemistry & pharma industry intelligence — for medicinal chemists, worldwide.https://themedchemdigest.com/enhttps://themedchemdigest.com/en/articles/2026-10-15-sanofi-eu-antitrust-flu-vaccine-commitments/https://themedchemdigest.com/en/articles/2026-10-15-sanofi-eu-antitrust-flu-vaccine-commitments/EU antitrust regulators accepted concessions from Sanofi to close a probe into an allegedly misleading campaign that disparaged a rival flu vaccine. Because the case ended on accepted commitments, Sanofi avoids a fine. Details of the commitments are behind STAT's paywall; this summary rests on the public excerpt only.Thu, 15 Oct 2026 00:00:00 GMTbusinessSanofiantitrustvaccinesEUhttps://themedchemdigest.com/en/articles/2026-10-15-chd4-macrocycle-nurd-interaction-hub/https://themedchemdigest.com/en/articles/2026-10-15-chd4-macrocycle-nurd-interaction-hub/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.Thu, 15 Oct 2026 00:00:00 GMTsciencemacrocyclesmRNA displayprotein-protein interactionfetal hemoglobinhttps://themedchemdigest.com/en/articles/2026-10-15-cinchona-ammonium-long-acting-nerve-block/https://themedchemdigest.com/en/articles/2026-10-15-cinchona-ammonium-long-acting-nerve-block/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.Thu, 15 Oct 2026 00:00:00 GMTsciencelocal anestheticsnatural productssodium channelpainhttps://themedchemdigest.com/en/articles/2026-10-15-lrrk2-g2019s-selective-octahydrocyclopentapyrrole/https://themedchemdigest.com/en/articles/2026-10-15-lrrk2-g2019s-selective-octahydrocyclopentapyrrole/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.Thu, 15 Oct 2026 00:00:00 GMTscienceLRRK2kinase inhibitorParkinson's diseasemutant selectivityhttps://themedchemdigest.com/en/articles/2026-10-15-oral-stat6-degrader-ww-210-atopic-dermatitis/https://themedchemdigest.com/en/articles/2026-10-15-oral-stat6-degrader-ww-210-atopic-dermatitis/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.Thu, 15 Oct 2026 00:00:00 GMTsciencePROTACSTAT6atopic dermatitisoral degraderhttps://themedchemdigest.com/en/articles/2026-10-15-gtp-state-kras-g12c-covalent-keto-indolizine/https://themedchemdigest.com/en/articles/2026-10-15-gtp-state-kras-g12c-covalent-keto-indolizine/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.Thu, 15 Oct 2026 00:00:00 GMTscienceKRAScovalent inhibitorHTSoncologyhttps://themedchemdigest.com/en/articles/2026-10-15-covalent-fragment-lysine-shp2-latch-site/https://themedchemdigest.com/en/articles/2026-10-15-covalent-fragment-lysine-shp2-latch-site/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.Thu, 15 Oct 2026 00:00:00 GMTsciencecovalent fragmentslysine targetingSHP2FBDDhttps://themedchemdigest.com/en/articles/2026-10-15-del-ml-docking-cofolding-generalizability/https://themedchemdigest.com/en/articles/2026-10-15-del-ml-docking-cofolding-generalizability/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.Thu, 15 Oct 2026 00:00:00 GMTscienceDELmachine learningdockingbenchmarkcofoldinghttps://themedchemdigest.com/en/articles/2026-10-14-neurocrine-vykat-xr-prader-willi-safety-concerns/https://themedchemdigest.com/en/articles/2026-10-14-neurocrine-vykat-xr-prader-willi-safety-concerns/STAT reports growing alarm among patient advocates and some experts over the perceived risks of Neurocrine's rare disease drug Vykat XR (diazoxide choline) for Prader-Willi syndrome. Earlier coverage links the concern to fluid retention, respiratory and cardiac events in post-marketing reports, though causality has not been established. Neurocrine has said it keeps a favourable benefit-risk view and is working with the FDA and patient groups.Wed, 14 Oct 2026 00:00:00 GMTbusinessNeurocrineVykat XRPrader-Willi syndromedrug safetyhttps://themedchemdigest.com/en/articles/2026-10-14-benzothiophene-mprb-antivirulence-tuberculosis/https://themedchemdigest.com/en/articles/2026-10-14-benzothiophene-mprb-antivirulence-tuberculosis/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.Wed, 14 Oct 2026 00:00:00 GMTsciencetuberculosisantivirulencehistidine kinasebenzothiophenehttps://themedchemdigest.com/en/articles/2026-10-14-dcl1191-tfeb-inhibitor-from-eltrombopag/https://themedchemdigest.com/en/articles/2026-10-14-dcl1191-tfeb-inhibitor-from-eltrombopag/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.Wed, 14 Oct 2026 00:00:00 GMTscienceTFEBtranscription factorautophagydrug repurposinghttps://themedchemdigest.com/en/articles/2026-10-14-hdac6-l2-pocket-inhibitors-lung-cancer/https://themedchemdigest.com/en/articles/2026-10-14-hdac6-l2-pocket-inhibitors-lung-cancer/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.Wed, 14 Oct 2026 00:00:00 GMTscienceHDAC6structure-based designautophagylung cancerhttps://themedchemdigest.com/en/articles/2026-10-14-pdia3-n-hydroxyindole-carboxamide-antivirals/https://themedchemdigest.com/en/articles/2026-10-14-pdia3-n-hydroxyindole-carboxamide-antivirals/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.Wed, 14 Oct 2026 00:00:00 GMTsciencePDIA3host-targeted antiviralrespiratory virusescoronavirushttps://themedchemdigest.com/en/articles/2026-10-14-peptide-like-del-403200-compounds-diversity/https://themedchemdigest.com/en/articles/2026-10-14-peptide-like-del-403200-compounds-diversity/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.Wed, 14 Oct 2026 00:00:00 GMTscienceDELDNA-encoded librarylibrary designchemical spacehttps://themedchemdigest.com/en/articles/2026-10-14-pi4kiiib-hdac-dual-inhibitors-hcv/https://themedchemdigest.com/en/articles/2026-10-14-pi4kiiib-hdac-dual-inhibitors-hcv/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.Wed, 14 Oct 2026 00:00:00 GMTsciencePI4KIIIβHDACdual inhibitorhepatitis Chost-directedhttps://themedchemdigest.com/en/articles/2026-10-14-sting-inhibitor-d4-severe-acute-pancreatitis/https://themedchemdigest.com/en/articles/2026-10-14-sting-inhibitor-d4-severe-acute-pancreatitis/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.Wed, 14 Oct 2026 00:00:00 GMTscienceSTINGinflammationpancreatitisoral bioavailabilityhttps://themedchemdigest.com/en/articles/2026-10-14-tubulin-hdac8-dual-inhibitor-millepachine-ovarian/https://themedchemdigest.com/en/articles/2026-10-14-tubulin-hdac8-dual-inhibitor-millepachine-ovarian/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.Wed, 14 Oct 2026 00:00:00 GMTsciencetubulinHDAC8dual inhibitornatural productovarian cancerhttps://themedchemdigest.com/en/articles/2026-10-13-vhl-hdac6-protacs-solid-phase-linker-sar/https://themedchemdigest.com/en/articles/2026-10-13-vhl-hdac6-protacs-solid-phase-linker-sar/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.Tue, 13 Oct 2026 00:00:00 GMTsciencePROTACHDAC6VHLsolid-phase synthesishttps://themedchemdigest.com/en/articles/2026-10-13-ferulic-acid-protac-tlr4-degradation-endothelium/https://themedchemdigest.com/en/articles/2026-10-13-ferulic-acid-protac-tlr4-degradation-endothelium/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.Tue, 13 Oct 2026 00:00:00 GMTsciencePROTACTLR4natural productcardiovascularhttps://themedchemdigest.com/en/articles/2026-10-13-gpr183-g-protein-biased-agonist-tug-2604/https://themedchemdigest.com/en/articles/2026-10-13-gpr183-g-protein-biased-agonist-tug-2604/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.Tue, 13 Oct 2026 00:00:00 GMTscienceGPR183GPCRbiased agonisminflammationhttps://themedchemdigest.com/en/articles/2026-10-13-kdm6b-diaryl-pyrimidine-guanidine-cervical-cancer/https://themedchemdigest.com/en/articles/2026-10-13-kdm6b-diaryl-pyrimidine-guanidine-cervical-cancer/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.Tue, 13 Oct 2026 00:00:00 GMTscienceKDM6Bepigeneticscervical cancervirtual screeninghttps://themedchemdigest.com/en/articles/2026-10-13-mor-d3r-dual-target-ligands-ls01-64-opioid/https://themedchemdigest.com/en/articles/2026-10-13-mor-d3r-dual-target-ligands-ls01-64-opioid/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.Tue, 13 Oct 2026 00:00:00 GMTscienceopioidMORdopamine D3dual-target ligandshttps://themedchemdigest.com/en/articles/2026-10-13-stk33-inhibitors-cdd-3094-male-contraception/https://themedchemdigest.com/en/articles/2026-10-13-stk33-inhibitors-cdd-3094-male-contraception/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.Tue, 13 Oct 2026 00:00:00 GMTscienceSTK33kinase inhibitorsmale contraceptionSAR/SPRhttps://themedchemdigest.com/en/articles/2026-10-12-donepezil-based-dual-buche-faah-inhibitors/https://themedchemdigest.com/en/articles/2026-10-12-donepezil-based-dual-buche-faah-inhibitors/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.Mon, 12 Oct 2026 00:00:00 GMTsciencemulti-target ligandsBuChEFAAHAlzheimer's diseasedonepezilhttps://themedchemdigest.com/en/articles/2026-10-12-flexenn-gnn-binding-energy-disordered-proteins/https://themedchemdigest.com/en/articles/2026-10-12-flexenn-gnn-binding-energy-disordered-proteins/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.Mon, 12 Oct 2026 00:00:00 GMTsciencegraph neural networkbinding affinity predictionintrinsically disordered proteinscomputational screeninghttps://themedchemdigest.com/en/articles/2026-10-12-lrrk2-g2019s-selective-indazole-bicyclic/https://themedchemdigest.com/en/articles/2026-10-12-lrrk2-g2019s-selective-indazole-bicyclic/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.Mon, 12 Oct 2026 00:00:00 GMTscienceLRRK2Parkinson's diseasekinase inhibitorsstructure-guided designhttps://themedchemdigest.com/en/articles/2026-10-12-siderophore-ampicillin-conjugate-pseudomonas/https://themedchemdigest.com/en/articles/2026-10-12-siderophore-ampicillin-conjugate-pseudomonas/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.Mon, 12 Oct 2026 00:00:00 GMTsciencesiderophoreantibiotic conjugatesPseudomonas aeruginosaantimicrobial resistancehttps://themedchemdigest.com/en/articles/2026-10-12-life-biosciences-glaucoma-reprogramming-update/https://themedchemdigest.com/en/articles/2026-10-12-life-biosciences-glaucoma-reprogramming-update/Life Biosciences said three glaucoma patients have now received a single injection of its experimental cellular reprogramming drug. No serious adverse events were reported so far. Only the public lede was readable, so dose, follow-up length and efficacy readouts are unverified here.Mon, 12 Oct 2026 00:00:00 GMTbusinesscellular reprogrammingglaucomaclinical updateLife Bioscienceshttps://themedchemdigest.com/en/articles/2026-10-12-lactam-bridged-peptide-il-11-antagonist/https://themedchemdigest.com/en/articles/2026-10-12-lactam-bridged-peptide-il-11-antagonist/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.Mon, 12 Oct 2026 00:00:00 GMTscienceIL-11peptide therapeuticslactam bridgerenal fibrosishttps://themedchemdigest.com/en/articles/2026-10-12-lasb-hydroxamate-inhibitors-ktgs/https://themedchemdigest.com/en/articles/2026-10-12-lasb-hydroxamate-inhibitors-ktgs/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.Mon, 12 Oct 2026 00:00:00 GMTscienceLasBkinetic target-guided synthesisantivirulencehydroxamic acidsPseudomonas aeruginosahttps://themedchemdigest.com/en/articles/2026-10-12-masked-bisphosphonate-acid-sphingomyelinase-inhibitors/https://themedchemdigest.com/en/articles/2026-10-12-masked-bisphosphonate-acid-sphingomyelinase-inhibitors/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.Mon, 12 Oct 2026 00:00:00 GMTscienceacid sphingomyelinasebisphosphonateprodrug maskingcell permeabilityhttps://themedchemdigest.com/en/articles/2026-10-12-viatris-pacira-non-opioid-pain-acquisition/https://themedchemdigest.com/en/articles/2026-10-12-viatris-pacira-non-opioid-pain-acquisition/Viatris agreed to acquire Pacira BioSciences in an all-cash deal at $36.50 per share, a premium of roughly 45% to the last close. The prize is Pacira's non-opioid products EXPAREL for post-surgical pain and ZILRETTA for knee osteoarthritis pain, plus a knee OA gene therapy candidate. Closing is expected by the end of 2026, funded mainly from cash on hand.Mon, 12 Oct 2026 00:00:00 GMTbusinessM&Anon-opioid painViatrisPaciraEXPARELhttps://themedchemdigest.com/en/articles/2026-10-10-argenx-vyvgart-sjogrens-phase3-failure/https://themedchemdigest.com/en/articles/2026-10-10-argenx-vyvgart-sjogrens-phase3-failure/STAT reports that argenx said its blockbuster drug Vyvgart did not outperform placebo in a Phase 3 trial in patients with Sjögren's disease, a chronic autoimmune disorder. STAT frames it as an unusual setback for a franchise that has mostly succeeded in label expansion; detailed data were not visible in the public lede.Sat, 10 Oct 2026 00:00:00 GMTbusinessargenxVyvgartefgartigimodSjögren's diseaseFcRnhttps://themedchemdigest.com/en/articles/2026-10-10-brain-penetrant-colchicine-site-ligand-glioma/https://themedchemdigest.com/en/articles/2026-10-10-brain-penetrant-colchicine-site-ligand-glioma/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.Sat, 10 Oct 2026 00:00:00 GMTsciencetubulincolchicine sitegliomabrain penetrationSARhttps://themedchemdigest.com/en/articles/2026-10-10-dnmt1-protac-b7-liver-fibrosis/https://themedchemdigest.com/en/articles/2026-10-10-dnmt1-protac-b7-liver-fibrosis/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.Sat, 10 Oct 2026 00:00:00 GMTsciencePROTACDNMT1liver fibrosistargeted protein degradationhttps://themedchemdigest.com/en/articles/2026-10-10-enpp1-boronic-acid-inhibitors-ph-resilient/https://themedchemdigest.com/en/articles/2026-10-10-enpp1-boronic-acid-inhibitors-ph-resilient/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.Sat, 10 Oct 2026 00:00:00 GMTscienceENPP1STINGboronic acidcancer immunotherapyhttps://themedchemdigest.com/en/articles/2026-10-10-fragdockrl-reinforcement-learning-fragment-design/https://themedchemdigest.com/en/articles/2026-10-10-fragdockrl-reinforcement-learning-fragment-design/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.Sat, 10 Oct 2026 00:00:00 GMTsciencefragment-based designreinforcement learningtethered dockingvirtual synthesishttps://themedchemdigest.com/en/articles/2026-10-10-hdac2-selective-inhibitor-ktt-1-kinetics/https://themedchemdigest.com/en/articles/2026-10-10-hdac2-selective-inhibitor-ktt-1-kinetics/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.Sat, 10 Oct 2026 00:00:00 GMTscienceHDAC2binding kineticsX-ray crystallographyneurological disordershttps://themedchemdigest.com/en/articles/2026-10-10-hsp90b-chimeric-selective-inhibitors/https://themedchemdigest.com/en/articles/2026-10-10-hsp90b-chimeric-selective-inhibitors/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.Sat, 10 Oct 2026 00:00:00 GMTscienceHsp90βisoform selectivityindazolonelead optimizationhttps://themedchemdigest.com/en/articles/2026-10-10-maglistat-del-hit-magli-432-five-star-matrix/https://themedchemdigest.com/en/articles/2026-10-10-maglistat-del-hit-magli-432-five-star-matrix/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.Sat, 10 Oct 2026 00:00:00 GMTscienceDELMAGLneuroinflammationstructure-guided designhit-to-leadhttps://themedchemdigest.com/en/articles/2026-10-10-qpct-l-inhibitors-virtual-screening-bi-3614/https://themedchemdigest.com/en/articles/2026-10-10-qpct-l-inhibitors-virtual-screening-bi-3614/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.Sat, 10 Oct 2026 00:00:00 GMTsciencevirtual screeningQPCTQPCTLCD47-SIRPαhit identificationhttps://themedchemdigest.com/en/articles/2026-10-10-arrivent-furvent-phase3-firmonertinib-miss/https://themedchemdigest.com/en/articles/2026-10-10-arrivent-furvent-phase3-firmonertinib-miss/Fierce Biotech reports that ArriVent's phase 3 FURVENT trial of the EGFR inhibitor firmonertinib missed its primary progression-free survival endpoint by blinded central review in first-line EGFR exon 20 insertion NSCLC. The higher dose showed only a modest numerical edge over platinum chemotherapy and the lower dose did numerically worse, while investigator-assessed results looked more favorable. ArriVent's shares fell sharply on the news.Sat, 10 Oct 2026 00:00:00 GMTbusinessArriVentfirmonertinibEGFR exon 20NSCLCphase 3https://themedchemdigest.com/en/articles/2026-10-09-roche-defand-molecular-glue-discovery-deal/https://themedchemdigest.com/en/articles/2026-10-09-roche-defand-molecular-glue-discovery-deal/STAT reports Roche has signed a drug discovery deal with Chinese biotech Defand Therapeutics focused on molecular glue medicines. Only the public lede of the STAT+ article could be read, so financial terms and targets are unverified here.Fri, 09 Oct 2026 00:00:00 GMTbusinessmolecular gluepartnershipRocheChina biotechtargeted protein degradationhttps://themedchemdigest.com/en/articles/2026-10-09-docking-accuracy-vs-number-of-crystal-structures/https://themedchemdigest.com/en/articles/2026-10-09-docking-accuracy-vs-number-of-crystal-structures/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.Fri, 09 Oct 2026 00:00:00 GMTsciencedockingstructure-based designCOVID Moonshotpose predictioncomputationalhttps://themedchemdigest.com/en/articles/2026-10-09-forbion-raises-2-6-billion-fund/https://themedchemdigest.com/en/articles/2026-10-09-forbion-raises-2-6-billion-fund/STAT reports European venture firm Forbion has raised $2.6 billion, its largest fundraise to date. It is described as one of the largest in the region in recent years; fund structure and allocation were not visible in the public lede.Fri, 09 Oct 2026 00:00:00 GMTbusinessventure capitalForbionfinancingEuropehttps://themedchemdigest.com/en/articles/2026-10-09-frespaciguat-mk-5475-inhaled-sgc-stimulator/https://themedchemdigest.com/en/articles/2026-10-09-frespaciguat-mk-5475-inhaled-sgc-stimulator/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.Fri, 09 Oct 2026 00:00:00 GMTsciencesGCinhaledpulmonary hypertensionCOPDPK/PDhttps://themedchemdigest.com/en/articles/2026-10-09-merck-keytruda-subcutaneous-dutch-court-halt/https://themedchemdigest.com/en/articles/2026-10-09-merck-keytruda-subcutaneous-dutch-court-halt/STAT reports a Dutch court ordered Merck to stop manufacturing and marketing its subcutaneous Keytruda formulation in several European countries. Only the public lede was readable, so the plaintiff, grounds and scope are unverified here.Fri, 09 Oct 2026 00:00:00 GMTbusinessKeytrudasubcutaneouspatentMerckEuropehttps://themedchemdigest.com/en/articles/2026-10-09-perk-inhibitor-apl-11056-clinical-candidate/https://themedchemdigest.com/en/articles/2026-10-09-perk-inhibitor-apl-11056-clinical-candidate/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.Fri, 09 Oct 2026 00:00:00 GMTsciencePERKkinaseintegrated stress responselead optimizationLLEhttps://themedchemdigest.com/en/articles/2026-10-09-polq-polymerase-inhibitors-benzimidazoles-purines/https://themedchemdigest.com/en/articles/2026-10-09-polq-polymerase-inhibitors-benzimidazoles-purines/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.Fri, 09 Oct 2026 00:00:00 GMTsciencePOLQDNA repairsynthetic lethalityPARPoncologyhttps://themedchemdigest.com/en/articles/2026-10-09-sulfonium-echinocandins-cryptococcus/https://themedchemdigest.com/en/articles/2026-10-09-sulfonium-echinocandins-cryptococcus/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.Fri, 09 Oct 2026 00:00:00 GMTscienceechinocandinantifungalCryptococcuspneumocandinnatural product