LF0376

LF0376 is a potent, selective, and orally bioavailable small molecule inhibitor of Ubiquitin-Specific Protease 1 (USP1), developed by Shenzhen Lingfang Biopharmaceutical Technology. USP1 is a critical deubiquitinating enzyme that regulates the DNA damage response (DDR) pathway, specifically by deubiquitinating substrates such as FANCD2 and PCNA involved in the Fanconi Anemia pathway and translesion synthesis. By inhibiting USP1, LF0376 prevents the recycling of these proteins, leading to the accumulation of DNA damage and genomic instability. This mechanism induces synthetic lethality in cancer cells with existing DDR deficiencies, such as BRCA1/2 mutations or homologous recombination deficiency (HRD), and has shown potential in overcoming resistance to PARP inhibitors. LF0376 is currently being evaluated in Phase 1 clinical trials for the treatment of advanced solid tumors and lymphomas.