Products Cited in Publications Worldwide C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand 1 Protein–Protein Interaction

Joanna Klimek; Oskar Kruc; Joanna Ceklarz; Beata Kami ´nska; Bogdan Musielak; Robin van der Straat; Alexander Dömling; Tad A. Holak; Damian Muszak; Justyna Kalinowska-Tłu´scik; Łukasz Skalniak; Ewa Surmiak

DOI:

Abstract

The complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting are monoclonal antibody-based drugs, which have several limitations. Therefore, small molecule compounds are emerging as an attractive alternative that can potentially overcome the drawbacks of mAb-based therapy. In this article, we present a novel class of small molecule compounds based on the scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an core, an additional aromatic ring, and a solubilizing agent. Using molecular docking, we designed a series of final compounds, which were subsequently synthesized and tested in HTRF assay and NMR binding assay to evaluate their activity. In addition, we performed an in-depth analysis of the mutual arrangement of the phenyl rings of the terphenyl core within the binding pocket of PD-L1 and found several correlations between the plane angle values and the affinity of the compounds towards the .

Keywords

PD-L1 ; immune checkpoint ; small molecule inhibitor ; cancer ; C2-symmetrical ligands

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