Design, Synthesis, and Evaluation of -(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy .

Two series of novel -(biphenyl-3-ylmethoxy)nitrophenyl compounds ( and ) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC values ranging from 2.7 to 87.4 nM except compound , and compound displayed the best activity. Further experiments showed that bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, significantly promoted interferon-gamma secretion in a dose-dependent manner and . Especially, exhibited potent anticancer efficacy in an LLC-bearing allograft mouse model at a low dose of 5 mg/kg, which was more active than BMS-1018 (tumor growth inhibition rate: 48.5% vs 17.8%). A panel of immunohistochemistry and flow cytometry assays demonstrated that effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that is a promising PD-1/PD-L1 inhibitor worthy of further development.