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

  • J Med Chem. 2021 Aug 12;64(15):11614-11636. doi: 10.1021/acs.jmedchem.1c00957.
Damian Muszak  1 ,  Ewa Surmiak  1 ,  Jacek Plewka  2 ,  Katarzyna Magiera-Mularz  1 ,  Justyna Kocik-Krol  1 ,  Bogdan Musielak  1 ,  Dominik Sala  1 ,  Radoslaw Kitel  1 ,  Malgorzata Stec  3 ,  Kazimierz Weglarczyk  3 ,  Maciej Siedlar  3 ,  Alexander Dömling  4 ,  Lukasz Skalniak  1 ,  Tad A Holak  1
Affiliations
  • 1. Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland.
  • 2. Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Kraków, Poland.
  • 3. Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka 265, 30-663 Krakow, Poland.
  • 4. Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
PMID: 34313116 DOI: 10.1021/acs.jmedchem.1c00957
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.

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