ZM323881

ZM323881 is a potent and selective inhibitor of the kinase activity of the human vascular endothelial growth factor receptor 2 (VEGFR2/KDR). ZM323881 selectively inhibits VEGFR2 over VEGFR1 and other receptor tyrosine kinases with an IC50 = 2nM. ZM323881 inhibits VEGF-A-induced endothelial cell proliferation (IC(50) = 8 nM) and VEGF-R2 tyrosine phosphorylation in vitro. VEGF-A-mediated increases in vascular permeability in perfused mesenteric microvessels in vivo were reversibly abolished by both ZM323881 and the class III receptor tyrosine kinase inhibitor PTK787/ZK222584. ZM323881 alone did not cause any alteration. Premedication with ZM323881 or L-NAME decreased the dilatory effects of VEGF. ZM323881 (10 nM) completely blocks VEGF-induced VEGF promoter activity in SCC-9 cells. ZM323881 (10 nM) blocks VEGF stimulated Hif-1α protein accumulation in SCC-9 cells. ZM323881 (10 nM) blocks VEGF-induced Rac1 activation at 30 min in HUVECs. ZM323881 (10 nM) prevents Vav2 tyrosine phosphorylation in response to VEGF in HUVECs.