Next-Gen AOH1996 Analogs Sharpen the Attack on Cancer's PCNA Isoform
- 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.
💡 Points
Four pharmacophoric regions systematically walked — substituents, bioisosteres, linkers, and a scaffold hop — is a proper second-generation SAR campaign, not a token tweak. Pairing better cancer-cell potency with improved microsomal stability is what actually matters for a caPCNA-interaction disruptor, since these shallow, protein-interface-driven pockets are usually the first thing to fall apart metabolically.
Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA ↗