Abstract 4481: Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition

Abstract Recently, we have developed AOH1996, a small molecule PCNA ligand currently in phase I clinical trial, designed to selectively inhibit the functions of cancer-associated PCNA (caPCNA). Seeking to enhance the potency and selectivity of AOH1996, we conducted an exhaustive Structure-Activity-Relationship (SAR) investigation. Over 100 analogues of AOH1996 were synthesized, systematically modifying its three main components: the naphthyl group, glycine linker, and diphenyl ether. The glycine linker underwent substitution with various natural and unnatural amino acids, while the 1-naphthyl group saw replacements with diverse monocyclic and bicyclic aromatic groups, including quinoline and isoquinoline derivatives. The diphenyl ether moiety was extensively explored by substituting the bridging oxygen with different functional groups (sulfonyl, imido, sulfur, amide), substituting both phenyl rings with various functional groups (fluorine, chlorine, hydroxy, methoxy, methyl, trifluoromethyl), and adopting a nitrogen-walk approach on the terminal phenyl ring to evaluate critical ligand/caPCNA-binding positions. This meticulous effort resulted in the identification of several analogues, such as AOH1160S (featuring a diphenyl thioether group), AOH1996S-4CH3 (with a methyl group at the para-position of the terminal thiophenyl ring), and AOH1996-3CH3 (incorporating an m-methoxy function in the terminal phenyl ring and bridging oxygen), exhibiting similar or superior potency compared to AOH1996. The target binding of these analogues was verified by capturing the binary complex of the more polar version of these analogues in the crystal structure. The synthesis, characterization, and detailed biological activities of these promising AOH analogues will be thoroughly described. Citation Format: Pouya Haratipour, Maryam Zangi, Mahshid Yaghoubi, Long Gu, Jennifer Jossart, John J. Perry, Linda H. Malkas, Robert J. Hickey. Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition 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 4481.