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
  • 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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