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Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.

ABSTRACT: We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.

SUBMITTER: Muszak D

PROVIDER: S-EPMC8365601 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction.

Muszak Damian D Surmiak Ewa E Plewka Jacek J Magiera-Mularz Katarzyna K Kocik-Krol Justyna J Musielak Bogdan B Sala Dominik D Kitel Radoslaw R Stec Malgorzata M Weglarczyk Kazimierz K Siedlar Maciej M Dömling Alexander A Skalniak Lukasz L Holak Tad A TA

Journal of medicinal chemistry 20210727 15

We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using <i>in silico</i> docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify k ...[more]

PMID: 34313116

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