TY - JOUR
T1 - In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis
AU - Latham, Antony M.
AU - Kankanala, Jayakanth
AU - Fearnley, Gareth W.
AU - Gage, Matthew C.
AU - Kearney, Mark T.
AU - Homer-Vanniasinkam, Shervanthi
AU - Wheatcroft, Stephen B.
AU - Fishwick, Colin W.G.
AU - Ponnambalam, Sreenivasan
N1 - Publisher Copyright:
© 2014 Latham et al.
PY - 2014/11/13
Y1 - 2014/11/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84911864558&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84911864558&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0110997
DO - 10.1371/journal.pone.0110997
M3 - Article
C2 - 25393739
AN - SCOPUS:84911864558
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 11
M1 - e110997
ER -