Currently, in late-stage preclinical development, Debio 0432 is a small molecule with best-in-class potential that could be deployed to combat multiple tumor types. Through its potent and selective inhibition of USP1, a critical player in DNA damage repair (DDR) pathway, Debio 0432 has the potential to induce synthetic lethality in tumor types with underlying defects of DNA repair genes (such as BCRA1). ‘Synthetic lethality, a process in which alterations in at least two different genes result in cell death due to inability of repairing DNA defects, is a novel and promising cancer therapy.
Ubiquitin-Specific Protease 1 (USP1) Inhibitor
Forced arrest of DDR leading to apoptosis
Being researched in:
Initially discovered by Forma Therapeutics (acquired by Novo Nordisk) before being licensed to Debiopharm, Debio 0432 inhibits USP1 and thus disrupts DDR and genome integrity of cancerous cells.
Through translational and clinical investigation, Debiopharm will apply its DDR inhibition expertise to efficiently advance the development of Debio 0432 with the aim of producing a novel therapy that responds to the unmet needs of cancer patients.
DNA Damage Repair and its role in cancer
To be able to reproduce and spread, cancer cells use a very common mechanism that even healthy cells use to preserve DNA from being permanently damaged or changed by internal or external factors 5. To avoid the threat of DNA damage, several systems exist to detect and repair the lesions. DNA damage repair (DDR) consists of all proteins and processes ensuring that the cell cycle does not progress with damaged DNA. If DDR is successful, then the cell cycle can resume. Cell reproduction is a highly regulated process guaranteeing a faithful duplication of the genome once per cell cycle so if the damage cannot be removed, the cell commences a self-destruction program leading to cell death.
USP1 Sustains Cancer Through DNA repair
The USP family is one of the largest subfamily of deubiquitinases (DUB). Ubiquitin-specific protease 1 (USP1), in particular, is a nucleus-localized enzyme and a well-established component of DNA repair, acting both in the Fanconi Anemia pathway (on FANCD2 and FANC1) and in translesion synthesis (TLS) on PCNA (Proliferating Cell Nuclear Antigen) substrate. It catalyzes the removal of specific monoubiquitin signals, is a critical regulator of genome integrity and its dysfunction plays a key role in cancer initiation and progression,[2-3] explaining why USP1 has recently drawn special attention as cancer target. In addition, USP1 was recently identified as a novel synthetic lethal interaction partner with BRCA1 loss offering a good rationale for the investigation of USP1 inhibitors in patient populations currently treated with PARP inhibitors. The potential of this class of new therapeutic agents might however be exploited in further settings as understanding of USP1 biology is progressing.
 Pal, Anupama et al. Emerging potential of therapeutic targeting of ubiquitin-specific proteases in the treatment of cancer. Cancer research vol. 74,18 (2014): 4955-66.
 Kah Suan Lim, Heng Li, Emma A Roberts, Emily F Gaudiano, Connor Clairmont, Larissa Alina Sambel, Karthikeyan Ponnienselvan, Jessica C Liu, Chunyu Yang, David Kozono, Kalindi Parmar, Timur Yusufzai, Ning Zheng, Alan D D’Andrea. USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors. Mol Cell 2018 Dec 20;72(6):925-941
 Are CRISPR Screens Providing the Next Generation of Therapeutic Targets? Vazquez F, Sellers WR. Cancer Res. 2021 Dec 1;81(23):5806-5809.
 USP1-trapping lesions as a source of DNA replication stress and genomic instability. Kate E Coleman, Yandong Yin, Sarah Kit Leng Lui, Sarah Keegan, David Fenyo, Duncan J Smith, Eli Rothenberg, Tony T Huang Nat Commun. 2022 Apr 1;13(1):1740.
 Lindahl T, Barnes DE. Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol. 2000; 65:127–133. An excellent overview of the extent of endogenous DNA damage, the types of DNA lesions arising from cell-autonomous sources, and the pathways that repair such lesions. [PubMed: 12760027]