Design, Synthesis, and Evaluation of PD-1/PD-L1 Antagonists Bearing a Benzamide Scaffold

  • ACS Med Chem Lett. 2022 Mar 29;13(4):586-592. doi: 10.1021/acsmedchemlett.1c00646.
Lu Lu  1 ,  Zhihao Qi  1 ,  Tianyu Wang  1 ,  Xiangyu Zhang  1 ,  Kuojun Zhang  1 ,  Kaizhen Wang  1 ,  Yao Cheng  1 ,  Yibei Xiao  1 ,  Zheng Li  2 ,  Sheng Jiang  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry and Department of Biomedical Engineering, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Center for Bioenergetics, Houston Methodist Research Institute, 6670 Bertner, Houston, Texas 77030, United States.
PMID: 35450381 DOI: 10.1021/acsmedchemlett.1c00646
Abstract

Several antibodies targeting programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) have been approved by the U.S. Food and Drug Administration (FDA) for Cancer therapy. Although many small-molecule inhibitors of the PD-1/PD-L1 pathway have been reported, no small-molecule inhibitors have been approved for Cancer treatment. In this work, a series of novel benzamide derivatives were designed, synthesized, and evaluated to find effective inhibitors of the PD-1/PD-L1 interaction. The most potent compound D2 exhibited better activity than that of BMS202, with an IC50 of 16.17 nM. D2 could activate the antitumor immunity of T cells efficiently in PBMCs. The proposed binding mode of compound D2 was investigated by docking analysis. These results indicate that compound D2 is a promising lead compound that can be used for further development.

Products