Dual PARP/NAMPT Inhibitors for BRCA Wild-Type Triple-Negative Breast Cancer: Disrupting Homologous Recombination Repair and Activating Antitumor Immunity.

Simultaneously inhibiting PARP and NAMPT has demonstrated synergistic efficacy in BRCA wild-type TNBC through synthetic lethality, offering a promising strategy to broaden the clinical utility of PARP inhibitors. Here, we report the rational design and optimization of novel dual PARP/NAMPT inhibitors. Compound 10n with potent, dual PARP1 and NAMPT inhibition (IC50 = 1.2 and 6.7 nM, respectively) effectively inhibited the proliferation of BRCA wild-type TNBC cells at nanomolar levels. Mechanically, 10n disrupted the homologous recombination repair pathway, caused the accumulation of DNA double-strand breaks and ultimately induced apoptosis. In vivo, 10n·HCl exhibited excellent antitumor efficacy in an MDA-MB-231 xenograft model, and strongly inhibited lung metastasis in a 4T1 metastatic model. Moreover, 10n·HCl provoked immunogenic cell death (ICD) and activated the cGAS-STING pathway, thereby stimulating antitumor immunity. These results establish 10n as a promising lead compound for the development of dual PARP/NAMPT inhibitors to treat BRCA wild-type TNBC.