Abstract 7145: Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy

Abstract

Abstract Introduction: Debio 0432 is a Ubiquitin Specific Protease 1 (USP1) inhibitor at preclinical stage. This study presents the first data on this small molecule and its activity as an anti-cancer therapy in multiple preclinical models. USP1 is a deubiquitinase, member of the deubiquitinating enzyme (DUB) family that plays an important role at the replication fork during DNA replication. Its prominent role in DNA repair, targeting Proliferating Cell Nuclear Antigen (PCNA) that regulates polymerase recruitment in the translesion synthesis (TLS), makes it an emergent target in the DNA damage repair (DDR) field. Methods: In silico docking has been used to identify a likely binding site of Debio 0432. Biochemical and cellular assays have been performed to show its activity on the target and in cell lines of different cancer types. In vivo models in cell line derived xenograft (CDX) and patient derived xenograft (PDX) were then used to confirm the activity of the compound and to study PK/PD relationship. Results: Debio 0432 likely binds USP1 in an allosteric pocket and is very selective across the 58 members of the USP family. Furthermore, it does not affect any kinase. Its biochemical activity on USP1 is in the low nanomolar range and cellular activity ranges between from single digit nM to above 1uM. In vivo, Debio 0432 shows antitumor activity in the BRCA mutant breast cancer model MDA-MB-436. The downstream target Ub-PCNA, selected as pharmacodynamic marker, is modulated in a dose and plasma exposure-dependent manner. Further in vivo experiments in PDX models showed dose-dependent activity in different cancer types, in both BRCA wild type and mutant models. Treatments in all in vivo studies were well tolerated. Conclusion: Overall, we show that Debio 0432 is a selective and potent small molecule targeting USP1, an emerging target in the DDR field. It shows good activity in different preclinical models and is well tolerated at active doses. Debio 0432 is currently undergoing IND-enabling studies and in preparation for entry into clinical development. Citation Format: Noemie Luong, Annett Kunze, Nicolas Quesnot, Erin R. Aho, Loren Berry, Scott Boiko, Alex J. Buckmelter, Sebastien Lofek, Selena Vigano, Christophe Chardonnens. Identification of Debio 0432 as a potent and selective USP1 inhibitor for cancer therapy [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(6_Suppl):Abstract nr 7145.