Design and synthesis of c-Met/PARP dual-target inhibitors for the treatment of BRCA wild-type TNBC.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options. Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have been approved for the treatment of various types of breast cancer gene 1/2 (BRCA1/2) mutated cancers, but approximately 80% of TNBC patients do not have BRCA mutations. Leveraging the effects of other targets on synthetic lethal interactions may be an effective way to broaden the indication of PARP1 inhibitors for TNBC patients with wild-type BRCA. Herein, a series of novel c-Met/PARP dual-target inhibitors based on the moiety of Olaparib were designed and synthesized. Among them, compound L19 potently inhibited c-Met and PARP1 at nanomolar levels and exhibited remarkable antiproliferative activity in BRCA wild-type TNBC cell lines. Meanwhile, compound L19 showed favorable synergistic anti-tumor efficacy in cells by promoting cell cycle arrest and apoptosis. In particular, L19 exhibited good in vivo antitumor activity (tumor growth inhibition (TGI) rate = 32%) in MDA-MB-231 xenograft models with low toxicity. Taken together, our designed dual c-Met/PARP inhibitors are novel and promising agents for the treatment of BRCA wild-type TNBC.