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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

B7-H1 Antigen*/antagonists & inhibitors ; B7-H1 Antigen*/metabolism ; B7-H1 Antigen*/chemistry ; Programmed Cell Death 1 Receptor*/antagonists & inhibitors ; Programmed Cell Death 1 Receptor*/metabolism ; Programmed Cell Death 1 Receptor*/chemistry ; Molecular Docking Simulation* ; Protein Binding* ; Terphenyl Compounds*/chemistry ; Terphenyl Compounds*/pharmacology; Humans ; Small Molecule Libraries/pharmacology ; Small Molecule Libraries/chemistry ; Immune Checkpoint Inhibitors/chemistry ; Immune Checkpoint Inhibitors/pharmacology ; Molecular Structure ; Structure-Activity Relationship ; Binding Sites

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.

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UMO-2020/37/N/ST4/02691 National Science Center; POIR.04.04.00-00-420F/17-00 Foundation for Polish Science; POIR.04.02.00-00-D001/20 European Union in the framework of the Smart Growth Operational Program, Measure 4.2; Priority Research Area SciMat Strategic Programme Excellence Initiative at Jagiellonian University

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

0 (B7-H1 Antigen)
0 (Programmed Cell Death 1 Receptor)
0 (Terphenyl Compounds)
0 (CD274 protein, human)
0 (Small Molecule Libraries)
0 (PDCD1 protein, human)
0 (Immune Checkpoint Inhibitors)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240708

20240708

PMC11173618

10.3390/molecules29112646

38893521