In Silico Design and Biological Evaluation of a Dual Specificity Kinase Inhibitor Targeting Cell Cycle Progression and Angiogenesis |
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Authors: | Antony M. Latham Jayakanth Kankanala Gareth W. Fearnley Matthew C. Gage Mark T. Kearney Shervanthi Homer-Vanniasinkam Stephen B. Wheatcroft Colin W. G. Fishwick Sreenivasan Ponnambalam |
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Affiliation: | 1. Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.; 2. School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom.; 3. Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine & Health, University of Leeds, Leeds LS2 9JT, United Kingdom.; University of Bari Medical School, Italy, |
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Abstract: | BackgroundProtein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.MethodologyWe have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.ConclusionsWe deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery. |
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