XL309

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.

P1, N=377, Recruiting, Exelixis | N=66 --> 377 | Trial completion date: Dec 2025 --> Aug 2029 | Trial primary completion date: Jul 2024 --> Jan 2029

P1, N=66, Not yet recruiting, InSilico Medicine Hong Kong Limited

In vitro data revealed that the combination of ISM3091 and olaparib, a PARPi, had synergistic activity in cell lines with HRD. ISM3091also displayed very favorable ADME propertiesand PK profiles, and GLP toxicology studies indicated that it was well tolerated without significant gastrointestinal toxicity or hematological toxicity. These data support the future clinical development of ISM3091 as a potential best-in-class USP1 inhibitor not only for PARPi-resistant/responsive HRD-mutant cancers, both, as a single agent as well as in combination with PARPi, but also for subsets of HR-proficient cancers.