Anti‐angiogenic and anti‐tumor effects of

摘要

We recently reported that TAK‐593, a novel imidazo[1,2‐b]pyridazine derivative, is a highly potent and selective inhibitor of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor tyrosine kinase families. Moreover, TAK‐593 exhibits a uniquely long‐acting inhibitory profile towards VEGF receptor 2 (VEGFR2) and PDGF receptor β (PDGFRβ). In this study, we demonstrated that TAK‐593 potently inhibits VEGF‐ and PDGF‐stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells. TAK‐593 also potently inhibits VEGF‐induced tube formation of endothelial cells co‐cultured with fibroblasts. Oral administration of TAK‐593 exhibited strong anti‐tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure. Even after the blood and tissue concentrations of TAK‐593 decreased below the detectable limit, a pharmacodynamic marker (phospho VEGFR2) was almost completely suppressed, indicating that its long duration of enzyme inhibition might contribute to the potent activity of TAK‐593. Immunohistochemical staining indicated that TAK‐593 showed anti‐proliferative and pro‐apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo. Furthermore, dynamic contrast‐enhanced magnetic resonance imaging revealed that TAK‐593 reduced tumor vessel permeability prior to the onset of anti‐tumor activity. In conclusion, TAK‐593 is an extremely potent VEGFR/PDGFR kinase inhibitor whose potent anti‐angiogenic activity suggests therapeutic potential for the treatment of solid tumors.