Portal de Periódicos da CAPES

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

2021; American Chemical Society; Volume: 64; Issue: 15 Linguagem: Inglês

10.1021/acs.jmedchem.1c00957

1520-4804

Damian Muszak, Ewa Surmiak, Jacek Plewka, Katarzyna Magiera‐Mularz, Justyna Kocik, Bogdan Musielak, Dominik Sala, Radosław Kitel, Małgorzata Stec, Kazimierz Węglarczyk, Maciej Siedlar, Alexander Dömlingꝉ, Łukasz Skalniak, Tad A. Holak,

Pharmacological Receptor Mechanisms and Effects

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.