Abstract 5124: Identification and structural characterization of a novel PCNA-interacting small molecule scaffold

Abstract Proliferating cell nuclear antigen (PCNA) plays essential roles in DNA replication, repair, transcription, and cell-cycle regulation, making it an attractive yet historically difficult target in cancer therapy. Building on our development of AOH1996, a first-in-class small molecule currently in Phase I clinical evaluation for solid and liquid tumors, we sought to identify additional PCNA-interacting chemotypes that could expand therapeutic opportunities and inform next-generation inhibitor design. Using an artificial intelligence-guided computer-aided drug discovery workflow, we screened more than ten million drug-like compounds and prioritized candidates through differential scanning fluorimetry. This approach led to the identification of COH005, a previously unreported small-molecule scaffold that binds PCNA. X-ray crystallography demonstrated that COH005 engages the major PCNA-interacting-protein (PIP)-box binding pocket, a critical interface for PCNA-mediated protein-protein interactions. Cellular thermal shift assays (CETSA) validated direct COH005-PCNA engagement in cells similar to clinical IND, AOH1996. To assess selectivity, we performed protein-structure frustration analysis comparing COH005 interactions with PCNA against an unrelated anti-target, revealing energetically favorable binding unique to PCNA. Together, these studies establish COH005 as a novel PCNA-interacting scaffold with strong potential for therapeutic development. This work provides a structural and mechanistic foundation for designing next-generation PCNA-targeted agents with improved specificity and pharmacological properties. Citation Format: Jennifer Jossart, Ning Ma, Pouya Haratipour, Caroline Li, Long Gu, Terrence O'Brien, Nagarajan Vaidehi, Linda H. Malkas, Robert Hickey, Jeff J. Perry. Identification and structural characterization of a novel PCNA-interacting small molecule scaffold abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5124.