Products Cited in Publications Worldwide Solubilizer Tag Effect on PD-L1/Inhibitor Binding Properties for m-Terphenyl Derivatives

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

Surmiak, Ewa; Zaber, Julia; Plewka, Jacek; Wojtanowicz, Grzegorz; Kocik-Krol, Justyna; Kruc, Oskar; Muszak, Damian; Rodriguez, Ismael; Musielak, Bogdan; Viviano, Monica; Castellano, Sabrina; Skalniak, Lukasz; Magiera-Mularz, Katarzyna; Holak, Tad A.; Kalinowska-Tluscik, Justyna

DOI: PMID:

Abstract

Although heavily studied, the subject of anti-PD-L1 small-mol. inhibitors is still elusive. Here, we present a systematic overview of the principles behind the successful anti-PD-L1 small mol. 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 the PD-1/PD-L1 complex formation in HTRF and cell-based assays. The affinity is also explained based on the crystal structure of the inhibitor itself, its costructure with PD-L1 as well as mol. 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.

Keywords

PD-L1 ; Immune checkpoint ; Small-molecule inhibitor ; Cancer ; m-Terphenyl

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