LF0397

LF0397 is a potent and highly selective small molecule inhibitor of Ubiquitin-Specific Protease 1 (USP1), developed by Shenzhen Lingfang Biopharmaceutical Technology Co., Ltd. USP1 is a critical deubiquitinating enzyme in the DNA damage response (DDR) pathway, where it regulates the monoubiquitination of Proliferating Cell Nuclear Antigen (PCNA) and the Fanconi Anemia complex member FANCD2. By inhibiting USP1, LF0397 prevents the removal of ubiquitin from these substrates, thereby disrupting DNA translesion synthesis and Fanconi Anemia-mediated repair mechanisms. This disruption leads to the accumulation of DNA damage and induces synthetic lethality in cancer cells that already possess deficiencies in homologous recombination repair (HRR), such as those with BRCA1 or BRCA2 mutations. LF0397 is currently being evaluated in Phase 1 clinical trials for the treatment of advanced solid tumors, both as a monotherapy and potentially in combination with other DDR-targeting agents.