Design, Synthesis and Biological Evaluation of Oxadiazole-Biphenyl Derivatives as Small Molecule Inhibitors Targeting PD-1/PD-L1 Immune Checkpoint

Monoclonal antibodies (mAbs) targeting programmed cell death protein-1 and its ligand 1 (PD-1/PD-L1) have demonstrated significant efficacy in cancer immunotherapy. However, mAbs still have limitations in pharmacokinetic properties and immunogenicity. As a complementary approach, PD-1/PD-L1 small molecule inhibitors have thus become an attractive direction for development. In this study, a series of novel small molecule compounds based on an oxadiazole-biphenyl scaffold were designed and synthesized. Biological evaluation showed that compound III-4 exhibited the most potent activity of the PD-1/PD-L1 interaction (IC 50 = 5.3 nM). At the cellular level, III-4 significantly enhanced the immune-killing activity of peripheral blood mononuclear cells (PBMCs) against MDA-MB-231 tumor cells and restored T-cell immune function by promoting IFN-γ secretion. These results indicate that compound III-4 is a promising PD-1/PD-L1 small molecule inhibitor for further development and optimization.