Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy,Journal of Medicinal Chemistry

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Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on the Fragment Coupling Strategy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-18 , DOI: 10.1021/acs.jmedchem.3c01534
Kaizhen Wang ₁ , Xiangyu Zhang ₁ , Yao Cheng ₁ , Zhihao Qi ₁ , Ke Ye ₁ , Kuojun Zhang ₁ , Sheng Jiang ₁ , Yi Liu ₁ , Yibei Xiao ₁ , Tianyu Wang ₁

Affiliation

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.

中文翻译：

基于片段偶联策略发现诱导 PD-L1 二聚化、内化和降解的新型 PD-L1 抑制剂

肿瘤细胞可以通过过度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在不与PD-1相互作用的情况下参与肿瘤进展，这为PD-L1抑制剂的发现提供了更多挑战。在此，我们报告了使用片段偶联策略发现的新型 PD-L1 抑制剂。其中， B9被发现可抑制PD-1/PD-L1相互作用，最佳IC ₅₀值为1.8 ± 0.7 nM。除了阻断 PD-1/PD-L1 轴之外， 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功效，并激活免疫微环境并诱导肿瘤中PD-L1的PD-L1降解。这些结果表明， B9通过阻断 PD-1/PD-L1 相互作用和功能性抑制 PD-L1 信号通路，成为一种有前景的先导 PD-L1 抑制剂。

更新日期：2023-12-18

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