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Identification of Small‐Molecule Inhibitors of PD‐1/PD‐L1 Protein‐Protein Interaction
Author(s) -
Patil Sachin P.,
Fink Madison A.,
Enley Erika S.,
Fisher James E.,
Herb Marie C.,
Klingos Anthony,
Proulx James T.,
Fedorky Megan T.
Publication year - 2018
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201800095
Subject(s) - protein–protein interaction , small molecule , pd l1 , chemistry , virtual screening , programmed cell death , ligand (biochemistry) , molecule , protein ligand , immune system , computational biology , cell , drug discovery , cancer research , biochemistry , apoptosis , immunotherapy , biology , receptor , immunology , organic chemistry
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.