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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Alison L Reynolds
  • Yolanda Alvarez
  • Temitope Sasore
  • Nora Waghorne
  • Clare Butler
  • Claire Kilty
  • Andrew J Smith
  • Carmel McVicar
  • Vickie Hy Wong
  • Orla Galvin
  • Stephanie Merrigan
  • Janina Osman
  • Gleb Grebnev
  • Anita Sjölander
  • Alan W Stitt
  • Breandán N Kennedy
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
JournalJournal of Biological Chemistry
Early online date2016 Feb 4
Publication statusPublished - 2016
Publication categoryResearch
Peer-reviewedYes