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

Reynolds, Alison L; Alvarez, Yolanda; Sasore, Temitope; Waghorne, Nora; Butler, Clare; Kilty, Claire; Smith, Andrew J; McVicar, Carmel; Wong, Vickie Hy and Galvin, Orla, et al. (2016) In Journal of Biological Chemistry
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... (More)
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. (Less)
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Journal of Biological Chemistry
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ASBMB
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  • pmid:26846851
  • scopus:84963979800
  • wos:000383447600004
ISSN
1083-351X
DOI
10.1074/jbc.M115.710665
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English
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yes
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61ca1d7f-1f7d-489b-81a3-c3781cdae02d (old id 8829275)
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http://www.ncbi.nlm.nih.gov/pubmed/26846851?dopt=Abstract
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2016-03-01 13:59:19
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2017-08-06 04:44:16
@article{61ca1d7f-1f7d-489b-81a3-c3781cdae02d,
  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.},
  author       = {Reynolds, Alison L and Alvarez, Yolanda and Sasore, Temitope and Waghorne, Nora and Butler, Clare and Kilty, Claire and Smith, Andrew J and McVicar, Carmel and Wong, Vickie Hy and Galvin, Orla and Merrigan, Stephanie and Osman, Janina and Grebnev, Gleb and Sjölander, Anita and Stitt, Alan W and Kennedy, Breandán N},
  issn         = {1083-351X},
  language     = {eng},
  month        = {02},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis.},
  url          = {http://dx.doi.org/10.1074/jbc.M115.710665},
  year         = {2016},
}