American Chemical Society
jm1c00370_si_001.pdf (4.73 MB)

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

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journal contribution
posted on 2021-05-26, 17:14 authored by Yiqiang OuYang, Jian Gao, Lei Zhao, Junfeng Lu, Haiqing Zhong, Hua Tang, Shuanglong Jin, Lu Yue, Yuezhen Li, Wenjie Guo, Qiang Xu, Yisheng Lai
Two series of novel o-(biphenyl-3-ylmethoxy)­nitrophenyl compounds (A1–31 and B1–17) were designed as programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) inhibitors. All compounds showed significant inhibitory activity with IC50 values ranging from 2.7 to 87.4 nM except compound A17, and compound B2 displayed the best activity. Further experiments showed that B2 bound to the PD-L1 protein without obvious toxicity in Lewis lung carcinoma (LLC) cells. Furthermore, B2 significantly promoted interferon-gamma secretion in a dose-dependent manner in vitro and in vivo. Especially, B2 exhibited potent in vivo 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 B2 effectively counteracted PD-1-induced immunosuppression in the tumor microenvironment, thereby triggering antitumor immunity. These results indicate that B2 is a promising PD-1/PD-L1 inhibitor worthy of further development.