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8633056 
Journal Article 
Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein-Protein Interaction 
Muszak, D; Surmiak, E; Plewka, J; Magiera-Mularz, K; Kocik-Krol, J; Musielak, B; Sala, D; Kitel, R; Stec, M; Weglarczyk, K; Siedlar, M; Dömling, A; Skalniak, L; Holak, TA 
2021 
Yes 
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 
English 
34313116 
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.