PUBLICATION
Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis
- Authors
- Reynolds, A.L., Alvarez, Y., Sasore, T., Waghorne, N., Butler, C., Kilty, C., Smith, A.J., McVicar, C., Wong, V.H., Galvin, O., Merrigan, S., Osman, J., Grebnev, G., Sjölander, A., Stitt, A.W., Kennedy, B.N.
- ID
- ZDB-PUB-160206-6
- Date
- 2016
- Source
- The Journal of biological chemistry 291(14): 7242-55 (Journal)
- Registered Authors
- Alvarez, Yolanda, Kennedy, Breandan N.
- Keywords
- G protein-coupled receptor (GPCR), angiogenesis, blindness, drug discovery, eye, hyaloid vasculature development, leukotriene, ocular angogenesis
- MeSH Terms
-
- Angiogenesis Inhibitors*/chemistry
- Angiogenesis Inhibitors*/pharmacokinetics
- Angiogenesis Inhibitors*/pharmacology
- Animals
- Animals, Genetically Modified
- Cell Line
- Diabetic Retinopathy/drug therapy
- Diabetic Retinopathy/metabolism
- Drug Discovery*
- Humans
- Macular Degeneration/drug therapy
- Macular Degeneration/metabolism
- Mice
- Phenols*/chemistry
- Phenols*/pharmacokinetics
- Phenols*/pharmacology
- Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
- Retinal Neovascularization/drug therapy*
- Retinal Neovascularization/metabolism
- Retinal Neovascularization/pathology
- Signal Transduction/drug effects*
- Zebrafish
- PubMed
- 26846851 Full text @ J. Biol. Chem.
Citation
Reynolds, A.L., Alvarez, Y., Sasore, T., Waghorne, N., Butler, C., Kilty, C., Smith, A.J., McVicar, C., Wong, V.H., Galvin, O., Merrigan, S., Osman, J., Grebnev, G., Sjölander, A., Stitt, A.W., Kennedy, B.N. (2016) Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis. The Journal of biological chemistry. 291(14):7242-55.
Abstract
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 neovascularisation. Phenotype-based chemical screens were performed using the ChemBridge Diverset™ 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 revascularisation in OIR mice. Quininib is well tolerated in zebrafish, human cell lines and murine eyes. Profiling screens of 153 angiogenic and inflammatory targets revealed quininib does not directly target VEGF receptors but antagonises cysteinyl leukotriene receptor 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 signalling. Quininib has potential as a novel therapeutic to treat ocular neovascular pathologies and may complement current anti-VEGF biologicals.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping