Abstract LB270: VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers

Abstract

Abstract Tumors characterized by deficiencies in DNA double-strand break (DSB) repair mechanisms, such as those harboring mutations in BRCA1/2, are commonly addressed through the administration of poly (ADP-ribose) polymerase-1 (PARP1) inhibitors or platinum-based chemotherapy. While these treatments offer clinical advantages, a significant number of patients eventually develop resistance, underscoring the necessity for innovative therapeutic strategies. USP1 belongs to the ubiquitin-specific processing (UBP) family of proteases, playing a pivotal role in modulating DNA damage response (DDR) pathways. VRTX531 is a novel potent, selective and allosteric inhibitor of USP1 with an IC50 of <50 nm in tested across a broad range of tumor lineages including MDAMB-436 and cell lines and UWB1.289. VRTX531, compound induces cell death through a pathway that is distinct from PARP inhibitors and compound demonstrates robust synergy when combined with first- or second-generation PARP inhibitors. Moreover, the compound exhibited profound activity alone and in combination with PARP inhibitor in BRCA1/2 mut and HRD+ tumors. VRTX531 exhibited exemplary pharmacokinetics and safety in preclinical studies and is expected to enter preclinical testing in H1, 2024. VRTX531 is being evaluated as a single agent and in combination with PARP1 inhibitor in patients with BRCA1/2 mut or HRD+ tumors that are naïve to PARP inhibitors and with prior PARP inhibitor history. Citation Format: Uday Kumar Surampudi, Prashant Kashinath Bhavar. VRTX531, a potent and selective inhibitor of USP1 for treatment of BRAC1/2mut and HRD+ cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB270.