Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

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Title: Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis
Authors: Reynolds, Alison
Alvarez, Yolanda
Sasore, Temitope
Waghorne, Nora
Butler, Clare T.
Kilty, Claire
Smith, Andrew J.
Galvin, Orla
Merrigan, Stephanie
Grebnev, Gleb
Kennedy, Breandán
et al.
Permanent link: http://hdl.handle.net/10197/9315
Date: 1-Apr-2016
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 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.
Funding Details: Health Research Board
Science Foundation Ireland
Type of material: Journal Article
Publisher: American Society for Biochemistry and Molecular Biology
Copyright (published version): 2016 The American Society for Biochemistry and Molecular Biology
Keywords: Angiogenesis;Drug discovery;Eye;G protein-coupled receptor (GPCR);Leukotriene;Blindness;Hyaloid vasculature development;Ocular angiogenesis
DOI: 10.1074/jbc.M115.710665
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Biomolecular and Biomedical Science Research Collection

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