Identification of Small‐Molecule Inhibitors of PD‐1/PD‐L1 Protein‐Protein Interaction
Sachin P. Patil, Madison A. Fink, Erika S. Enley, James E. Fisher, Marie C. Herb, Anthony Klingos, James T. Proulx, Megan T. Fedorky · ChemistrySelect · 2018
Abstract The protein‐protein interaction between programmed cell death protein 1 (PD‐1) and programmed cell death ligand 1 (PD−L1) proteins is one of the major checkpoint inhibition pathways responsible for the escape of tumors from immune destruction. Therefore, inhibition of the PD‐1/PD−L1 interaction presents an important therapeutic target against such tumors that express PD−L1 on their cell surface. Herein, we report structure‐based virtual screening of the National Cancer Institute Diversity Set compounds leading to the identification of several small‐molecule inhibitors of PD‐1/PD−L1 interaction. Top 4 molecules significantly inhibited PD‐1/PD−L1 interaction in a dose‐dependent manner, with the most active molecule (NSC149050) exhibiting ∼50% inhibition at 25 μM test concentration. This is remarkable considering it has a relatively low molecular weight and still is capable of inhibiting PD‐1/PD−L1 protein‐protein interaction whose binding interface spans over ∼1.970 Å 2 . Thus, these molecules may prove well suited for lead optimization studies leading to design of more potent analogs with improved drug‐like properties against this traditionally challenging anticancer target.