In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis

Protein 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, balan...

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Bibliographic Details
Published in:	PloS one 2014-11, Vol.9 (11), p.e110997
Main Authors:	Latham, Antony M, Kankanala, Jayakanth, Fearnley, Gareth W, Gage, Matthew C, Kearney, Mark T, Homer-Vanniasinkam, Shervanthi, Wheatcroft, Stephen B, Fishwick, Colin W G, Ponnambalam, Sreenivasan
Format:	Article
Language:	eng
Subjects:	Angiogenesis Angiogenesis Inhibitors - pharmacology Aniline Compounds - pharmacology Animals Anticancer properties Biology and Life Sciences Breast cancer Breast Neoplasms - blood supply Breast Neoplasms - drug therapy Breast Neoplasms - pathology Cancer CDC2 Protein Kinase - antagonists & inhibitors Cell adhesion & migration Cell culture Cell cycle Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cyclin B Cyclin-dependent kinase Cyclin-dependent kinases Design Drug Design Drug development Drug discovery Endothelial cells Endothelial Cells - drug effects Enzyme inhibitors Female Humans Inhibitors Kinases Male MCF-7 Cells Medicine and Health Sciences Metastases Mice Mice, Inbred C57BL Neoplasm Metastasis - drug therapy Neovascularization, Pathologic - drug therapy Neovascularization, Physiologic - drug effects Protein Kinase Inhibitors - pharmacology Proteins Rodents Signal transduction Signal Transduction - drug effects Signaling Toxicity Triazoles - pharmacology Vascular endothelial growth factor Vascular endothelial growth factor receptor 2 Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Wound Healing - drug effects
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Summary:	Protein 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. We 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. We 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.
ISSN:	1932-6203 1932-6203