AIG07025的发现及临床前表征：一种具有广泛联合潜力的强效选择性USP1抑制剂

USP1 is an emerging synthetic lethality target in cancers characterized by heightened replication stress, including tumors with BRCA mutations or homologous recombination deficiency (HRD). Although PARP inhibitors are the standard of care for BRCA/HRD-positive cancers, their clinical utility is frequently limited by acquired resistance mechanisms such as BRCA reversion mutations, rewiring of DNA repair pathways, and drug efflux. Targeting USP1, which regulates DNA damage repair and replication fork stability through a pathway distinct from PARP, represents a promising alternative strategy to overcome resistance in BRCA/HRD-driven tumors. AIG07025 exhibited potent in vitro antitumor activity across a diverse panel of cancer cell lines, with marked sensitivity in models driven by BRCA mutations or homologous recombination deficiency (HRD). Consistent with its mechanism of action, USP1 inhibition by AIG07025 induced strong and reproducible synergistic interactions with multiple agents targeting distinct DNA damage response and replication stress pathways, extending beyond PARP inhibition. In in vivo studies, AIG07025 delivered robust and durable antitumor efficacy in both subcutaneous xenograft and orthotopic metastasis models. The compound demonstrated favorable drug-like properties and was well tolerated in a 2-week repeated-dose toxicity study in CD-1 mice, with no clinically meaningful treatment-related findings in clinical chemistry, hematology, or major organ histopathology at most dose levels. Collectively, these data establish AIG07025 as a differentiated and highly selective USP1 inhibitor with broad combination potential and support its continued development for the treatment of BRCA/HRD-driven cancers. IND-enabling studies are currently ongoing.