Second-Generation AOH1996 Analogues Show Improved Potency Against Cancer-Associated PCNA
- 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.
- The real headline isn't the potency bump — it's that the PIP-box pocket, a shallow PPI interface people wrote off as undruggable, actually supports systematic SAR across four independent pharmacophore regions. That's a proper chemotype, not a lucky HTS hit. - Getting better cellular potency AND better microsomal stability out of substituent/bioisostere/linker/scaffold-hop work is the signal I want at this stage — potency alone would leave me wondering if you'd just traded one metabolic liability for another. - "Selective for caPCNA" is a claim I'll hold loosely until I see a real therapeutic index — normal-cell counterscreens and in vivo tox, not just cancer-line IC50s. The acidic-isoform story is attractive but easy to oversell. - Still, beating first-gen AOH1996 on both axes is the right trajectory for a second-gen PPI series.
Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA ↗