Design, Synthesis, and Biological Evaluation of Chroman Derivatives as PD-1/PD-L1 Antagonists

  • J Chem Inf Model. 2024 Jun 24;64(12):4877-4896. doi: 10.1021/acs.jcim.4c00455.
Luosen Wang  1 ,  Jie Hou  1 ,  Peng Cao  1 ,  Zhiying Yao  1 ,  Shijun Wang  1 ,  Yuying Zhang  1 ,  Sheng Wang  2 ,  Haoliang Yuan  1 ,  Liu Liu  1
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Center for Scientific Research, Anhui Medical University, Hefei 230000, China.
PMID: 38856697 DOI: 10.1021/acs.jcim.4c00455
Abstract

Programmed death-ligand 1 (PD-L1) has emerged as a promising therapeutic target for various cancers due to its crucial role in promoting tumor immune evasion. Here, we report a novel class of chroman-like small-molecule PD-L1 inhibitors exhibiting significant activity in inhibiting the PD-1/PD-L1 interaction. Employing a "ring-close" strategy for conformational restriction, we have achieved compound C27, which demonstrates superior PD-1/PD-L1 inhibitory activity compared to the positive control. Molecular dynamics simulation and binding free energy calculation predict that (R)-C27 with inhibitory activity surpassed (S)-C27. The experimental results from bioassay and X-ray structural analysis corroborate these findings. All these results collectively indicate that (R)-C27 is a promising lead compound deserving further exploration.

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