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

Several antibodies targeting programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) have beenapproved by the U.S. Food and Drug Administration (FDA) forcancer therapy. Although many small-molecule inhibitors of thePD-1/PD-L1 pathway have been reported, no small-moleculeinhibitors have been approved for cancer treatment. In this work, aseries of novel benzamide derivatives were designed, synthesized,and evaluated tofind effective inhibitors of the PD-1/PD-L1interaction. The most potent compoundD2exhibited betteractivity than that of BMS202, with an IC50of 16.17 nM.D2couldactivate the antitumor immunity of T cells efficiently in PBMCs. The proposed binding mode of compoundD2was investigated bydocking analysis. These results indicate that compoundD2is a promising lead compound that can be used for further development