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Kilty, Claire
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Kilty, Claire
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Kilty, Claire
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Now showing 1 - 3 of 3
- PublicationStructure-activity relationship of a novel family of cysteinyl leukotriene receptor antagonist quinoline compounds with anti-angiogenic activity(British Pharmacological Society, 2017-04-01)
; ; ; ; ; ; ; ; ; ; ; Introduction: Previously, we identified quininib (2-[(E)-2-(quinolin-2-yl)vinyl]phenol), a cysteinyl leukotriene receptor antagonist with anti-angiogenic and anti-permeable activity (1,2). Here, we report a structure activity relationship study to more comprehensively characterise features which confer anti-angiogenic activity.21 - PublicationInhibition of the Pim1 Oncogene Results in Diminished Visual Function(Public Library of Science, 2012-12-26)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Our objective was to profile genetic pathways whose differential expression correlates with maturation of visual function in zebrafish. Bioinformatic analysis of transcriptomic data revealed Jak-Stat signalling as the pathway most enriched in the eye, as visual function develops. Real-time PCR, western blotting, immunohistochemistry and in situ hybridization data confirm that multiple Jak-Stat pathway genes are up-regulated in the zebrafish eye between 3-5 days post-fertilisation, times associated with significant maturation of vision. One of the most up-regulated Jak-Stat genes is the proto-oncogene Pim1 kinase, previously associated with haematological malignancies and cancer. Loss of function experiments using Pim1 morpholinos or Pim1 inhibitors results in significant diminishment of visual behaviour and function. In summary, we have identified that enhanced expression of Jak-Stat pathway genes correlates with maturation of visual function and that the Pim1 oncogene is required for normal visual function.279Scopus© Citations 20 - PublicationPhenotype-based Discovery of 2-[(E)-2-(Quinolin-2-yl)vinyl]phenol as a Novel Regulator of Ocular Angiogenesis(American Society for Biochemistry and Molecular Biology, 2016-04-01)
; ; ; ; ; ; ; ; ; ; ; 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.350Scopus© Citations 29