Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m -Terphenyl Derivatives.
- Resource Type
- Academic Journal
- Authors
- Surmiak E; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Ząber J; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, 30-348 Cracow, Poland.; Plewka J; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Wojtanowicz G; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Kocik-Krol J; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, 30-348 Cracow, Poland.; Kruc O; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, 30-348 Cracow, Poland.; Muszak D; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Rodríguez I; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Doctoral School of Exact and Natural Sciences, Jagiellonian University, Łojasiewicza 11, 30-348 Cracow, Poland.; Musielak B; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Viviano M; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84085 Fisciano, Italy.; Castellano S; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84085 Fisciano, Italy.; Skalniak L; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Magiera-Mularz K; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Holak TA; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.; Kalinowska-Tłuścik J; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Cracow, Poland.
- Source
- Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE
- Subject
- Language
- English
- ISSN
- 1948-5875
Although heavily studied, the subject of anti-PD-L1 small-molecule inhibitors is still elusive. Here we present a systematic overview of the principles behind successful anti-PD-L1 small-molecule inhibitor design on the example of the m -terphenyl scaffold, with a particular focus on the neglected influence of the solubilizer tag on the overall affinity toward PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking PD-1/PD-L1 complex formation in homogeneous time-resolved fluorescence and cell-based assays. The affinity is also explained based on the crystal structure of the inhibitor itself and its costructure with PD-L1 as well as a molecular modeling study. Our results structuralize the knowledge related to the strong pharmacophore feature of the m -terphenyl scaffold preferential geometry and the more complex role of the solubilizer tag in PD-L1 homodimer stabilization.
Competing Interests: The authors declare no competing financial interest.
(© 2023 The Authors. Published by American Chemical Society.)