Design, Synthesis, and Evaluation of o-(Biphenyl-3-ylmethoxy)nitrophenyl Derivatives as PD-1/PD-L1 Inhibitors with Potent Anticancer Efficacy In Vivo
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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邻(联苯-3-基甲氧基)硝基苯基衍生物作为PD-1/PD-L1抑制剂的设计、合成和评估，具有体内有效的抗癌功效
DOI：
10.1021/acs.jmedchem.1c00370
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发表时间：
2021-05-26
影响因子：
7.3
通讯作者：
Lai, Yisheng
中科院分区：
文献类型：
--
作者：
OuYang, Yiqiang;Gao, Jian;Lai, Yisheng
设计了两个系列的新型o-（联苯-3-基甲氧基）硝基苯化合物（A1-31和B1-17）作为程序性细胞死亡蛋白1 (PD-1)/ PD-L1配体1 （PD-L1）抑制剂。除化合物A17外，其余化合物的IC50值均在2.7 ~ 87.4 nM之间，其中化合物B2的IC50值最高。进一步实验表明，B2与PD-L1蛋白结合对Lewis肺癌（LLC）细胞无明显毒性。此外，B2在体外和体内均以剂量依赖性的方式显著促进干扰素分泌。特别是，B2在低剂量5 mg/kg时，对携带llc的同种异体移植小鼠模型具有较强的体内抗癌作用，其活性高于BMS-1018（肿瘤生长抑制率：48.5% vs 17.8%）。一组免疫组织化学和流式细胞术分析表明，B2有效地抵消了pd -1在肿瘤微环境中引起的免疫抑制，从而引发抗肿瘤免疫。这些结果表明，B2是一种有前景的PD-1/PD-L1抑制剂，值得进一步开发。
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.