USP1 inhibition: A journey from target discovery to clinical translation

Ubiquitin-specific protease 1 (USP1) is a deubiquitinating enzyme involved in the DNA damage response. Upon DNA damage, USP1 stabilizes replication forks by removing monoubiquitin from PCNA and FANCD2-FANCI, thereby catalyzing critical final steps in translesion synthesis and interstrand crosslink (ICL) repair. This function is particularly crucial in BRCA1 mutant cancers, where the homologous recombination pathway is compromised, leading tumors to rely on USP1 for effective repair. USP1 is also overexpressed in BRCA1 mutant cancers, as well as other tumor types. Preclinical studies have demonstrated that knockout of USP1 is synthetically lethal in tumors with biallelic BRCA1 mutations, and this relationship is enhanced by combination with PARP inhibitors. Newly developed USP1 inhibitors have confirmed this synthetic lethality in BRCA1-deficient tumor cells. Moreover, these drugs have the potential for resensitizing platinum-resistant tumors. Currently, potent and specific USP1 inhibitors are undergoing evaluation in phase I clinical trials. RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. Other USP1 inhibitors, including SIM0501, XL309–101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors.