Solubilizer tag effect on PD-L1/inhibitor binding properties for m-terphenyl derivatives

Abstract

Although heavily studied, the subject of anti-PD-L1 small molecular inhibitors is still elusive. Here, we present a systematic overview of principles behind the 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 towards PD-L1. The inhibitor developed according to the proposed guidelines was characterized through its potency in blocking 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 co-structure with PD-L1 as well as 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.