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

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Methodology: 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.

Conclusions: 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 antiangiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

Background: 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.

Original languageEnglish (US)
Article numbere110997
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 13 2014

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