Synthesis and Evaluation of Biphenyl-1,2,3-Triazol-Benzonitrile Derivatives as PD-1/PD-L1 Inhibitors

[Image: see text] In this study, we designed and synthesized a series of 3-(4-((5-((2-methylbiphenyl-3-yl) methoxy)-2-(piperazin-1-ylmethyl)phenoxy)methyl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives and examined the effect of the compounds on the interaction between PD-1 and PD-L1. Among the newly synthesized compounds, compound 7 exhibited the most potent inhibitory activity for PD-1/PD-L1 binding, with an IC(50) value being 8.52 μM, through homogeneous time-resolved fluorescence (HTRF) assay. Docking studies indicated that compound 7 can very well interact with PD-L1 dimerization like BMS-202 as a positive control, consistent with the results of the HTRF assay. Compound 7 is thus a promising candidate for further optimization as an inhibitor of the PD-1/PD-L1 signaling pathway.