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


METHODS
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 anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.
Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Antony M
AM
Latham
School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Jayakanth
J
Kankanala
Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Gareth W
GW
Fearnley
Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine & Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
Matthew C
MC
Gage
Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine & Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
Mark T
MT
Kearney
Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine & Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
Shervanthi
S
Homer-Vanniasinkam
Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine & Health, University of Leeds, Leeds LS2 9JT, United Kingdom.
Stephen B
SB
Wheatcroft
School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom.
Colin W G
CW
Fishwick
Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Sreenivasan
S
Ponnambalam
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; C000604513:N-phenyl-1H-1,2,4-triazole-3,5-diamine; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D040301:Vascular Endothelial Growth Factor Receptor-2; D016203:CDC2 Protein Kinase