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

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 Sjölander; Alan W Stitt; Breandán N Kennedy

doi:10.1074/jbc.M115.710665

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

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 Sjölander, Alan W Stitt, Breandán N Kennedy

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

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 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 (CysLT_1–2) 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.

Original language	English
Pages (from-to)	7242-7255
Number of pages	14
Journal	Journal of Biological Chemistry
Volume	291
Issue number	14
Early online date	04 Feb 2016
DOIs	https://doi.org/10.1074/jbc.M115.710665
Publication status	Published - 01 Apr 2016

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Alan Stitt
- a.stittqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Dean of Innovation and Impact
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Reynolds, A. L., Alvarez, Y., Sasore, T., Waghorne, N., Butler, C. T., Kilty, C., Smith, A. J., McVicar, C., Wong, V. H. Y., Galvin, O., Merrigan, S., Osman, J., Grebnev, G., Sjölander, A., Stitt, A. W., & Kennedy, B. N. (2016). Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis. Journal of Biological Chemistry, 291(14), 7242-7255. https://doi.org/10.1074/jbc.M115.710665

@article{44c347cf98f2416c9fa4c84b893392fc,

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 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.",

author = "Reynolds, {Alison L} and Yolanda Alvarez and Temitope Sasore and Nora Waghorne and Butler, {Clare T.} and Claire Kilty and Smith, {Andrew J} and Carmel McVicar and Wong, {Vickie H. Y.} and Orla Galvin and Stephanie Merrigan and Janina Osman and Gleb Grebnev and Anita Sj{\"o}lander and Stitt, {Alan W} and Kennedy, {Breand{\'a}n N}",

year = "2016",

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doi = "10.1074/jbc.M115.710665",

language = "English",

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Reynolds, AL, Alvarez, Y, Sasore, T, Waghorne, N, Butler, CT, Kilty, C, Smith, AJ, McVicar, C, Wong, VHY, Galvin, O, Merrigan, S, Osman, J, Grebnev, G, Sjölander, A, Stitt, AW & Kennedy, BN 2016, 'Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis', Journal of Biological Chemistry, vol. 291, no. 14, pp. 7242-7255. https://doi.org/10.1074/jbc.M115.710665

TY - JOUR

T1 - Phenotype-Based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis

AU - Reynolds, Alison L

AU - Alvarez, Yolanda

AU - Sasore, Temitope

AU - Waghorne, Nora

AU - Butler, Clare T.

AU - Kilty, Claire

AU - Smith, Andrew J

AU - McVicar, Carmel

AU - Wong, Vickie H. Y.

AU - Galvin, Orla

AU - Merrigan, Stephanie

AU - Osman, Janina

AU - Grebnev, Gleb

AU - Sjölander, Anita

AU - Stitt, Alan W

AU - Kennedy, Breandán N

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M115.710665

DO - 10.1074/jbc.M115.710665

M3 - Article

C2 - 26846851

SN - 0021-9258

VL - 291

SP - 7242

EP - 7255

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 14

ER -

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

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