State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, Texas 77030, United States.
J Med Chem. 2021 Jun 10;64(11):7390-7403. doi: 10.1021/acs.jmedchem.1c00010. Epub 2021 May 30.
With the successful clinical application of anti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies (mAb), targeting the PD-1/PD-L1 interaction has become a promising method for the discovery of cancer therapy. Due to the inherent limitations of antibodies, it is necessary to search for small-molecule inhibitors against the PD-1/PD-L1 axis. We report the design, synthesis, and evaluation and of a series of novel biphenyl pyridines as the inhibitors of PD-1/PD-L1. 2-(((2-Methoxy-6-(2-methyl-[1,1'-biphenyl]-3-yl)pyridin-3-yl)methyl)amino)ethan-1-ol () was found to inhibit the PD-1/PD-L1 interaction with an IC value of 3.8 ± 0.3 nM and enhance the killing activity of tumor cells by immune cells. Compound displays great pharmacokinetics (oral bioavailability of 22%) and significant antitumor activity in a CT26 mouse model. Flow cytometry and immunohistochemistry data indicated that compound activates the immune activity in tumors. These results suggest that compound is a promising small-molecule inhibitor against the PD-1/PD-L1 axis and merits further development.
随着抗程序性细胞死亡蛋白-1（PD-1）/程序性细胞死亡配体 1（PD-L1）单克隆抗体（mAb）的成功临床应用，针对 PD-1/PD-L1 相互作用的靶向治疗已成为癌症治疗的一种有前途的方法。由于抗体固有的局限性，有必要寻找针对 PD-1/PD-L1 轴的小分子抑制剂。我们报告了一系列新型联苯吡啶作为 PD-1/PD-L1 抑制剂的设计、合成和评价。发现 2-(((2-甲氧基-6-(2-甲基-[1,1'-联苯]-3-基)吡啶-3-基)甲基)氨基)乙醇 () 抑制 PD-1/PD-L1 相互作用的 IC 值为 3.8±0.3 nM，并增强免疫细胞对肿瘤细胞的杀伤活性。化合物 在 CT26 小鼠模型中具有良好的药代动力学（口服生物利用度为 22%）和显著的抗肿瘤活性。流式细胞术和免疫组织化学数据表明，化合物 在肿瘤中激活了免疫活性。这些结果表明，化合物 是一种有前途的针对 PD-1/PD-L1 轴的小分子抑制剂，值得进一步开发。
