title: Phenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis.
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 Diverset(TM)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 μmin 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 IC50values. 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.
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Alison L
authors: AL
authors: Reynolds
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Yolanda
authors: Y
authors: Alvarez
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Temitope
authors: T
authors: Sasore
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Nora
authors: N
authors: Waghorne
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Clare T
authors: CT
authors: Butler
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Claire
authors: C
authors: Kilty
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Andrew J
authors: AJ
authors: Smith
authors: the Centre for Experimental Medicine, Queen's University Belfast, Wellcome-Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom, and.
authors: Carmel
authors: C
authors: McVicar
authors: the Centre for Experimental Medicine, Queen's University Belfast, Wellcome-Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom, and.
authors: Vickie H Y
authors: VH
authors: Wong
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Orla
authors: O
authors: Galvin
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Stephanie
authors: S
authors: Merrigan
authors: the Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, 20502 Malmö, Sweden.
authors: Janina
authors: J
authors: Osman
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Gleb
authors: G
authors: Grebnev
authors: the Division of Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, 20502 Malmö, Sweden.
authors: Anita
authors: A
authors: Sjölander
authors: the Centre for Experimental Medicine, Queen's University Belfast, Wellcome-Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom, and.
authors: Alan W
authors: AW
authors: Stitt
authors: From the University College Dublin School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland, brendan.kennedy@ucd.ie.
authors: Breandán N
authors: BN
authors: Kennedy
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D010636:Phenols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D010636:Phenols; D011804:Quinolines; C000620980:quininib; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: G protein-coupled receptor (GPCR); angiogenesis; blindness; drug discovery; eye; hyaloid vasculature development; leukotriene; ocular angiogenesis