USP1 inhibitor(Shandong Xuanzhu Pharmaceutical)

Overcoming the immunosuppressive tumor microenvironment and therapeutic resistance remains a significant challenge in ovarian cancer treatment. In this study, a glutathione‐responsive polymeric nanoparticle platform for the co‐delivery of the USP1 inhibitor SJB3‐019A and the PARP inhibitor Niraparib is developed. This system synergistically enhances DNA damage accumulation, suppresses homologous recombination repair, and robustly activate the STING signaling pathway, leading to enhanced type I interferon responses and mitigation of immune evasion. Mechanistically, USP1 inhibition significantly impairs DNA repair, amplifying the synthetic lethality of PARP inhibition and promoting immunogenic cell death. In vivo studies demonstrated precise, glutathione‐responsive drug release and substantial tumor accumulation of the nanoparticles, resulting in remarkable antitumor efficacy in murine ovarian cancer models. Importantly, this combinational approach effectively remodels the tumor microenvironment by increasing CD8⁺ T cell infiltration and enhancing tumor sensitivity to immune checkpoint blockade therapies. This innovative strategy targeting DNA damage responses presents a promising platform for precise and effective ovarian cancer immunotherapy.

USP1 (ubiquitin-specific peptidase 1) is a deubiquitinating enzyme that has been identified as essential in BRCA1/2 mutant cells and implicated in the DNA damage response. Inhibition of USP1 by small molecule inhibitors disrupts DNA repair and replication and is being pursued as a potential anticancer therapeutic in BRCA1/2 mutant cancers. We report the discovery of an in vitro and in vivo USP1 inhibitor tool compound TNG-6132 (18), a reversible, allosteric inhibitor of USP1, which strongly inhibits USP1 enzymatic activity. This inhibitory effect translates into in vitro cellular viability defects in a BRCA1-mutant breast cancer cell line, as well as an in vivo pharmacodynamic (PD) response and tumor growth suppression in a mouse xenograft efficacy model. Additionally, we report an X-ray co-crystal structure of TNG-6132 (18) bound in the USP1-UAF1 complex, a result that furthered our understanding of the role played by key elements of the pharmacophore of this chemotype as well as its mechanism of inhibition of USP1.