Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis
| Autor: | Stephanie Merrigan, Orla Galvin, Anita Sjölander, Claire Kilty, Clare T. Butler, Nora Waghorne, Vickie H. Y. Wong, Breandán N. Kennedy, Carmel M. McVicar, Andrew Smith, Alison L. Reynolds, Temitope Sasore, Gleb Grebnev, Alan W. Stitt, Janina Osman, Yolanda Alvarez |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Angiogenesis Cell Angiogenesis Inhibitors Retinal Neovascularization Eye Blindness Biochemistry Animals Genetically Modified Macular Degeneration Mice chemistry.chemical_compound 0302 clinical medicine Drug Discovery Hyaloid vasculature development Receptor Zebrafish biology Drug discovery Molecular Bases of Disease 3. Good health Vascular endothelial growth factor medicine.anatomical_structure 030220 oncology & carcinogenesis Quinolines Signal transduction Signal Transduction Retinopathy Ocular angiogenesis Stereochemistry G protein-coupled receptor (GPCR) Cell Line 03 medical and health sciences Phenols medicine Animals Humans Molecular Biology Diabetic Retinopathy Retinal Cell Biology biology.organism_classification medicine.disease Receptors Vascular Endothelial Growth Factor 030104 developmental biology chemistry Cancer research Leukotriene |
| Zdroj: | Journal of Biological Chemistry. 291:7242-7255 |
| ISSN: | 0021-9258 |
| Popis: | Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge DiversetTM library and inhibition of hyaloid vessel angiogenesis in Tg(fli1:EGFP) zebrafish. 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol, (quininib) robustly inhibits developmental angiogenesis at 4–10 μm in zebrafish and significantly inhibits angiogenic tubule formation in HMEC-1 cells, angiogenic sprouting in aortic ring explants, and retinal revascularization in oxygen-induced retinopathy mice. Quininib is well tolerated in zebrafish, human cell lines, and murine eyes. Profiling screens of 153 angiogenic and inflammatory targets revealed that quininib does not directly target VEGF receptors but antagonizes cysteinyl leukotriene receptors 1 and 2 (CysLT1–2) at micromolar IC50 values. In summary, quininib is a novel anti-angiogenic small-molecule CysLT receptor antagonist. Quininib inhibits angiogenesis in a range of cell and tissue systems, revealing novel physiological roles for CysLT signaling. Quininib has potential as a novel therapeutic agent to treat ocular neovascular pathologies and may complement current anti-VEGF biological agents. Health Research Board Science Foundation Ireland Enterprise Ireland |
| Databáze: | OpenAIRE |
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