Design, Synthesis, and Evaluation of <i>o</i>-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy <i>In Vivo</i>.
OuYang Y, Gao J, Zhao L, Lu J, Zhong H, Tang H, Jin S, Yue L, Li Y, Guo W, Xu Q, Lai Y.
Two series of novel <i>o</i>-(biphenyl-3-ylmethoxy)nitrophenyl compounds (<b>A1-31</b> and <b>B1-17</b>) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC<sub>50</sub> values ranging from 2.7 to 87.4 nM except compound <b>A17</b>, and compound <b>B2</b> displayed the best activity. Further experiments showed that <b>B2</b> bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, <b>B2</b> significantly promoted interferon-gamma secretion in a dose-dependent manner <i>in vitro</i> and <i>in vivo</i>. Especially, <b>B2</b> exhibited potent <i>in vivo</i> 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 <b>B2</b> effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that <b>B2</b> is a promising PD-1/PD-L1 inhibitor worthy of further development.