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.
- Klíčová slova
- C2-symmetrical ligands, PD-L1, cancer, immune checkpoint, small molecule inhibitor,
- MeSH
- antigeny CD274 * antagonisté a inhibitory metabolismus chemie MeSH
- antigeny CD279 * antagonisté a inhibitory metabolismus chemie MeSH
- inhibitory kontrolních bodů chemie farmakologie MeSH
- knihovny malých molekul farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- simulace molekulového dockingu * MeSH
- terfenylové sloučeniny * chemie farmakologie MeSH
- vazba proteinů * MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny CD274 * MeSH
- antigeny CD279 * MeSH
- CD274 protein, human MeSH Prohlížeč
- inhibitory kontrolních bodů MeSH
- knihovny malých molekul MeSH
- PDCD1 protein, human MeSH Prohlížeč
- terfenylové sloučeniny * MeSH
