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

Lu Lu, Zhihao Qi, Tianyu Wang, Xiangyu Zhang, Kuojun Zhang, Kaizhen Wang, Yao Cheng, Yibei Xiao, Zheng Li, Sheng Jiang

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 IC50of 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.

Original languageEnglish (US)
Pages (from-to)586-592
Number of pages7
JournalACS Medicinal Chemistry Letters
Issue number4
StatePublished - Apr 14 2022


  • PD-1
  • PD-L1 inhibitor
  • immune checkpoint
  • small molecules inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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