KY386

KY386 is a potent, highly selective, and orally bioavailable small molecule inhibitor of Ubiquitin-specific-processing protease 1 (USP1), developed by Shenzhen Kaiyue Life Technology Co., Ltd. USP1 is a critical deubiquitinating enzyme in the DNA damage response (DDR) pathway, specifically regulating the monoubiquitination of FANCD2 and PCNA. By inhibiting USP1, KY386 prevents the deubiquitination of these substrates, thereby disrupting the Fanconi anemia pathway and translesion synthesis. This disruption leads to the accumulation of DNA damage and induces synthetic lethality in cancer cells with existing homologous recombination deficiencies (HRD), such as those harboring BRCA1/2 mutations. KY386 is currently in Phase 1 clinical development for the treatment of advanced solid tumors, including ovarian cancer and triple-negative breast cancer, where it is being evaluated as a monotherapy and in potential combination with PARP inhibitors.