Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment,Journal of Medicinal Chemistry

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Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-12-29 , DOI: 10.1021/acs.jmedchem.2c01801
Chengliang Sun _{1,

2,

3} , Mingxiao Yin ₄ , Yao Cheng _{1,

5} , Zean Kuang ₄ , Xiaojia Liu ₄ , Gefei Wang _{1,

2,

3} , Xiao Wang _{1,

2,

3} , Kai Yuan _{1,

2,

3} , Wenjian Min _{1,

2,

3} , Jingwen Dong ₄ , Yi Hou _{1,

2,

3} , Lingrong Hu _{1,

2,

3} , Guoyu Zhang _{1,

2,

3} , Wenli Pei _{1,

2,

3} , Liping Wang _{1,

2,

3} , Yanze Sun _{1,

2,

3} , Xinmiao Yu _{1,

2,

3} , Yibei Xiao _{1,

5} , Hongbin Deng ₄ , Peng Yang _{1,

2,

3}

Affiliation

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 S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 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. In vivo, S4-1 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, S4-1 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 S4-1 as an alternative ICB therapeutic strategy.

中文翻译：

新型小分子 PD-L1 抑制剂诱导 PD-L1 内化并优化免疫微环境

阻断PD-1/PD-L1相互作用已成为肿瘤治疗的重要策略，在临床中显示出良好的治疗效果。然而，不理想的缓解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S4-1的发现和鉴定，S4-1 是一种创新的 PD-L1 小分子抑制剂。在体外， S4-1有效改变PD-L1/PD-1相互作用，诱导PD-L1二聚化和内化，改善其在内质网的定位，从而增强外周血单个核细胞对肿瘤细胞的细胞毒性。在体内， S4-1显着抑制肺癌和结直肠癌模型中的肿瘤生长，特别是在结直肠癌中，它导致部分肿瘤细胞完全清除。此外， S4-1诱导 T 细胞激活并逆转抑制性肿瘤微环境，这与 PD-L1/PD-1 通路阻断一致。这些数据支持对S4-1作为替代 ICB 治疗策略的持续评估。

更新日期：2022-12-29

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