In-silico fragment-based identification of novel angiogenesis inhibitors

Inhibition of vascular endothelial growth factor receptor-2 (VEGFR2/KDR/Flk-1) 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/KDR/Flk-1 kinase, we undertook a computer assisted fragment-based screening that used 3-D structural models of the VEGFR2/KDR/Flk-1 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.