Abstract 6985: Discovery of potent and selective USP1 inhibitors for the treatments of BRCA-deficient tumors

Abstract Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are the first successfully approved synthetic lethal cancer treatments targeting BRCA1/2-mutated breast and ovarian cancers. However, limited responsiveness among patients with BRCA1/2 mutations and the emergence of resistance to PARP inhibitors highlight the growing need for alternative synthetic lethal drugs, either as monotherapy or in combination with PARP inhibitors. Ubiquitin-Specific Protease 1 (USP1), a member of the deubiquitinating enzyme (DUB) family, plays a crucial role in DNA repair processes. USP1 inhibitors induce cancer cell death by blocking Translesion Synthesis (TLS) and the Fanconi anemia pathway, both of which have been identified as synthetic lethal partners with BRCA1/2 mutations or other homologous recombination deficiencies (HRD). We identified HD-12093 and HD-12136 as potent and selective USP1 inhibitors. Both compounds exhibited strong potency in the BRCA1-mutant triple-negative breast cancer (TNBC) cell line, MDA-MB-436, and demonstrated excellent selectivity for BRCA1-mutant cells over BRCA wild-type cells. HD-12093 and HD-12136 also induced the accumulation of mono-ubiquitinated PCNA, a known substrate of USP1. In PARP inhibitor-resistant cells, these compounds showed synergistic growth-inhibitory effects when combined with a PARP inhibitor, highlighting their strong potential to effectively overcome PARP inhibitor resistance. HD-12093 and HD-12136 exhibit favorable drug-like properties and pharmacokinetic profiles suitable for once-daily oral administration. These results support further development of HD-12093 and HD-12136 as potential best-in-class USP1 inhibitors for BRCA-deficient cancers resistant to PARP inhibitors either as monotherapy or in combination with PARP inhibitors. Citation Format: Seong Heon Kim, Hwa Sil Kim, Sukho Lee, Jieun Kim, Jinwoo Lee, Jong Woo Park, Yukyung Kim, Daehoon Kim, Doo-Young Kim, Min Ah Park. Discovery of potent and selective USP1 inhibitors for the treatments of BRCA-deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6985.