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

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.

SUBMITTER: Lu L

PROVIDER: S-EPMC9014519 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Lu Lu L Qi Zhihao Z Wang Tianyu T Zhang Xiangyu X Zhang Kuojun K Wang Kaizhen K Cheng Yao Y Xiao Yibei Y Li Zheng Z Jiang Sheng S

ACS medicinal chemistry letters 20220329 4

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 ...[more]

PMID: 35450381

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