title: Anti-angiogenic and anti-tumor effects of TAK-593, a potent and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinase.
abstract: 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.
authors.affiliation: Inflammation Drug Discovery Unit, Fujisawa, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Awazu
authors.forename: Akio
authors.initials: A
authors.lastname: Mizutani
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagase
authors.forename: Shuntarou
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kakoi
authors.forename: Osamu
authors.initials: O
authors.lastname: Kitahara
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
authors.forename: Akira
authors.initials: A
authors.lastname: Hori
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D011720:Pyrazoles; C557405:TAK 593; D042461:Vascular Endothelial Growth Factor A; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor