Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m‑Terphenyl Derivatives

• Published in: ACS medicinal chemistry letters Vol. 15; no. 1; pp. 36 - 44
• Main Authors: Surmiak, Ewa, Ząber, Julia, Plewka, Jacek, Wojtanowicz, Grzegorz, Kocik-Krol, Justyna, Kruc, Oskar, Muszak, Damian, Rodríguez, Ismael, Musielak, Bogdan, Viviano, Monica, Castellano, Sabrina, Skalniak, Lukasz, Magiera-Mularz, Katarzyna, Holak, Tad A., Kalinowska-Tłuścik, Justyna
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.01.2024; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; PD-L1; Immune checkpoint; Small-molecule inhibitor; m-Terphenyl; Cancer; LIGANDS; SMALL-MOLECULE INHIBITORS; PD-1/PD-L1
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00306

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.