Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.
Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy.
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DOI：
10.1021/acs.jmedchem.3c01534
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发表时间：
2023-12
影响因子：
7.3
通讯作者：
Kaizhen Wang;Xiangyu Zhang;Yao Cheng;Zhihao Qi;Ke Ye;Kuojun Zhang;Sheng Jiang;Yi Liu;Yibei Xiao;Tianyu Wang
中科院分区：
文献类型：
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作者：
Kaizhen Wang;Xiangyu Zhang;Yao Cheng;Zhihao Qi;Ke Ye;Kuojun Zhang;Sheng Jiang;Yi Liu;Yibei Xiao;Tianyu Wang
肿瘤细胞可以通过过表达程序性细胞死亡配体1 （PD-L1）与程序性细胞死亡-1 （PD-1）相互作用来逃避免疫监视。此外，肿瘤固有的PD-L1参与肿瘤的进展而不与PD-1相互作用，这给PD-L1抑制剂的发现带来了更多的挑战。在此，我们报告了使用片段偶联策略的新型PD-L1抑制剂的发现。其中B9抑制PD-1/PD-L1相互作用，IC50值最佳为1.8±0.7 nM。除了阻断PD-1/PD-L1轴外，B9还促进PD-L1的二聚化、内化和降解。此外，B9在CT26小鼠模型中表现出较高的体内抗肿瘤效果，激活免疫微环境，诱导肿瘤中PD-L1的降解。这些结果表明，B9通过阻断PD-1/PD-L1相互作用和功能抑制PD-L1信号通路，是一种很有前景的PD-L1先导抑制剂。
Tumor cells can evade immune surveillance through overexpressing programmed cell death-ligand 1 (PD-L1) to interact with programmed cell death-1 (PD-1). Besides, tumor-intrinsic PD-L1 is involved in tumor progression without interaction with PD-1, which provides more challenges for the discovery of PD-L1 inhibitors. Herein, we report the discovery of novel PD-L1 inhibitors using the fragment coupling strategy. Among them, B9 was found to inhibit the PD-1/PD-L1 interaction with the best IC50 value of 1.8 ± 0.7 nM. Beyond the blockade of the PD-1/PD-L1 axis, B9 promotes the dimerization, internalization, and degradation of PD-L1. Furthermore, B9 displayed high in vivo antitumor efficacy in the CT26 mouse model and activated the immune microenvironment and induced PD-L1 degradation of PD-L1 in the tumor. These results show that B9 is a promising lead PD-L1 inhibitor through the blockade of PD-1/PD-L1 interaction and functional inhibition of the PD-L1 signal pathway.