2rl5

File:2rl5.jpg

Crystal structure of the VEGFR2 kinase domain in complex with a 2,3-dihydro-1,4-benzoxazine inhibitor

OverviewOverview

Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.

About this StructureAbout this Structure

2RL5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis., La DS, Belzile J, Bready JV, Coxon A, Demelfi T, Doerr N, Estrada J, Flynn JC, Flynn SR, Graceffa RF, Harriman SP, Larrow JF, Long AM, Martin MW, Morrison MJ, Patel VF, Roveto PM, Wang L, Weiss MM, Whittington DA, Teffera Y, Zhao Z, Polverino AJ, Harmange JC, J Med Chem. 2008 Mar 27;51(6):1695-705. Epub 2008 Feb 27. PMID:18311900