The PD-1/PD-L1 complex is an immune checkpoint responsible for regulating the natural immune response, but also allows tumors to escape immune surveillance. Inhibition of the PD-1/PD-L1 axis positively contributes to the efficacy of cancer treatment. The only available therapeutics targeting PD-1/PD-L1 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 terphenyl scaffold that bind to PD-L1. The general architecture of the presented structures is characterized by axial symmetry and consists of three elements: an m-terphenyl 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 protein.

Department of Drug Design University of Groningen 9713 AV Groningen The Netherlands

Department of Organic Chemistry Faculty of Chemistry Jagiellonian University Gronostajowa St 2 30 387 Cracow Poland

Doctoral School of Exact and Natural Sciences Jagiellonian University Prof St Łojasiewicza St 11 30 348 Cracow Poland

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry and Czech Advanced Technology and Research Institute Palackӯ University in Olomouc Křížkovského 511 8 779 00 Olomouc Czech Republic

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