2. Academic Validation
  3. Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment

Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment

  • J Med Chem. 2022 Dec 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
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 5 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
PMID: 36579489 DOI: 10.1021/acs.jmedchem.2c01801
Abstract

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.

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