State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem. 2023 Feb 9;66(3):2064-2083. doi: 10.1021/acs.jmedchem.2c01801. Epub 2022 Dec 29.
Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of , an innovative small-molecule inhibitor of PD-L1. , effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. , significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of as an alternative ICB therapeutic strategy.
阻断 PD-1/PD-L1 相互作用已成为肿瘤治疗的重要策略，在临床环境中已显示出突出的治疗效果。然而，不尽如人意的响应率和免疫相关的不良反应限制了抗 PD1/PD-L1 抗体的使用。在这里，我们报告了 PD-L1 的一种创新的小分子抑制剂 的发现和鉴定。 有效地改变了 PD-L1/PD-1 的相互作用，诱导 PD-L1 二聚化和内化，改善其向内质网的定位，从而增强外周血单核细胞对肿瘤细胞的细胞毒性。 在肺和结直肠癌模型中均显著抑制肿瘤生长，特别是在结直肠癌中，部分肿瘤细胞完全清除。此外， 诱导 T 细胞活化并逆转抑制性肿瘤微环境，与 PD-L1/PD-1 途径阻断一致。这些数据支持继续评估 作为一种替代 ICB 治疗策略。
