Abstract 6583: Developing a selective cancer chemotherapy by small molecule-based targeting of PCNA protein

Abstract Proliferating cell nuclear antigen (PCNA) is a proliferation biomarker in a variety of human tumors and has critical cellular functions in DNA replication and repair. We previously identified a unique cancer-associated isoform of the protein, termed caPCNA, which allows for structure-based drug discovery studies to develop inhibitors for selective therapeutic targeting of cancer cells. Distinct strategies have been used to develop caPCNA targeting agents, which includes peptide and small molecule-based compounds, although the success in developing therapeutically tractable compounds has been limited so far. Here, we present the crystal structures and corresponding biochemical characterizations of our novel small molecule-based caPCNA inhibitors, which bind into the PIP-box binding pocket of PCNA. Our lead compound selectively kills cancer cells, and it appears to induce replication stress, apoptosis and increase cancer cell sensitivity to genotoxic agents, while these effects are not observed in non-malignant cell controls. This caPCNA inhibitor is orally administrable, metabolic stable and it suppresses tumor growth as a monotherapy or as a combination treatment and is now an investigational new drug in Phase 1 clinical trials. PCNA plays a critical role enabling the replication fork to proceed from transcription replication conflict sites, by temporarily dislodging RNA polymerase II. Thus, structure-based drug discovery against caPCNA may open a novel therapeutic avenue for the development of selective chemotherapeutics, through targeting a cancer cell’s vulnerability to unresolved transcription replication conflicts. Citation Format: Jennifer Jossart, Long Gu, Pouya Haratipour, Caroline Li, Robert Lingeman, Robert Hickey, Linda Malkas, John J. Perry. Developing a selective cancer chemotherapy by small molecule-based targeting of PCNA protein abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6583.