Presented at AACR Annual Meeting 2024
Noemie Luong1, Annett Kunze1, Nicolas Quesnot1, Erin R. Aho2, Loren Berry2, Scott Boiko2, Alex J. Buckmelter2, Sebastien Lofek3, Selena Vigano3, Vincent Gerusz3 Christophe Chardonnens3
1. Debiopharm International SA, Switzerland.
2. Forma Therapeutics, United States
3. Debiopharm Research & Manufacturing SA, Switzerland
Summary
Ubiquitin Specific Protease 1 (USP1) is a member of the deubiquitinating enzyme (DUB) family that plays an important role in maintaining DNA integrity. USP1 plays an important role in DNA damage repair through its deubiquitinating activities on Fanconi Anemia proteins FANCI and FANCD2, required for DNA interstrand crosslink repair, and on Proliferating Cell Nuclear Antigen (PCNA) required for translesion synthesis (TLS)1. USP1 is upregulated in BRCA-mutated tumors and contributes to the stabilization of the replication fork during DNA replication. In those tumors, genetic deletion of USP1 is synthetically lethal2.
Debio 0432 is a USP1 inhibitor at preclinical stage. The molecule is predicted to bind USP1 in an allosteric pocket and is very selective among the 58 members of the DUB family. Debio 0432 biochemical activity on USP1 is below 1nM and >20x more potent than another USP1 inhibitor in development, KSQ-4279/RG-6614. Monotherapy activity has been observed in several cell lines, across several tumor types. In vivo, Debio 0432 shows antitumor activity in the BRCA mutant breast cancer model MDA-MB-436 and in the BRCA WT NCI-H292 lung cancer model. The downstream target Ub-PCNA, selected as pharmacodynamic marker, is modulated in a dose and plasma exposure-dependent manner. Further in vivo experiments in patient derived xenograft (PDX) models show anti-tumor activity in different cancer types. At active dose, the treatments in all in vivo studies are well tolerated.
Overall, we show that Debio 0432 is a selective and potent small molecule inhibitor of USP1, an emerging target for cancer therapy in the DDR field. It is currently undergoing IND-enabling studies.
References
1. Garcia-Santisteban et al., Molecular Cancer (2013) 12:91
2. Lim et al., 2018, Molecular Cell 72, 925-941