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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2016 Feb 6

PMID 26846851

Citations 20

Authors

Alison L Reynolds

Yolanda Alvarez

Temitope Sasore

Nora Waghorne

Clare T Butler

Claire Kilty

Andrew J Smith

Carmel McVicar

Vickie H Y Wong

Orla Galvin

Stephanie Merrigan

Janina Osman

Gleb Grebnev

Anita Sjolander

Alan W Stitt

Breandan N Kennedy

Affiliations

Soon will be listed here.

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.

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