In-silico fragment-based identification of novel angiogenesis inhibitors.
Inhibition of vascular endothelial growth factor receptor-2 (VEGFR2) kinase blocks angiogenesis, the process of generating new capillary blood vessels that are important in tumor growth. To identify small molecule inhibitors of the VEGFR2 kinase, we undertook a computer assisted fragment-based screening that used 3-D structural models of the VEGFR2 kinase, and hinge region as a fragment anchor point. Seven novel non-cytotoxic compounds were identified which limited the induction of capillary networks by human umbilical vein endothelial cells in the low micromolar range.
Dakshanamurthy
Sivanesan
S
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA. sd233@georgetown.edu
Kim
Min
M
Brown
Milton L
ML
Byers
Stephen W
SW
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002478:Cells, Cultured; D003198:Computer Simulation; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2