Terphenyl-based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein−Protein Interaction

Here, we report a novel class of potent PD-L1/PD-1 inhibitors based on the rigidified biphenyl-inspired structure – terphenyls. Using in-silico docking, we designed and later experimentally shown the efficacy of terphenyl-based scaffolds to inhibit the PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also report a high-resolution structure of the PD-L1 complex with our most potent inhibitors allowing the identification of key interactions with PD-L1 at the molecular level. Moreover, we show the efficacy of our most potent inhibitors at activating the antitumor response using primary T-cells derived from healthy donors. This effect was not observed even for the therapeutic antibodies. This makes our compounds prominent candidates for further optimization for anti-PD-L1 cancer treatments.