Terphenyl-based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein−Protein Interaction
2021
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.
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