For research use only. Not Intended for Therapeutic Use!
|IC50:||3.2/0.95/1.1 nM(VEGFR1/2/3); 4.3/1/13 nM(PDGFRα/PDGFRα V561D/PDGFRβ) |
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TAK-593 is a potent and selective dual VEGFR/PDGFR inhibitor with IC50s of 3.2/0.95/1.1 nM(VEGFR1/2/3) and 4.3/1/13 nM(PDGFRα/PDGFRα V561D/PDGFRβ); with an IC50 >1 μM when tested against more than 200 protein and lipid kinases.
IC50 value: 3.2/0.95/1.1 nM(VEGFR1/2/3); 4.3/1/13 nM(PDGFRα/PDGFRα V561D/PDGFRβ) 
in vitro: TAK-593, a novel imidazo[1,2-b]pyridazine derivative, potently inhibits tyrosine kinases from the VEGFR and PDGFR families. TAK-593 was highly selective for these families, with an IC(50) >1 μM when tested against more than 200 protein and lipid kinases. TAK-593 displayed competitive inhibition versus ATP. In addition, TAK-593 inhibited VEGFR2 and PDGFRβ in a time-dependent manner, classifying it as a type II kinase inhibitor. Analysis of enzyme-inhibitor preincubation experiments revealed that the binding of TAK-593 to VEGFR2 and PDGFRβ occurs via a two-step slow binding mechanism. Dissociation of TAK-593 from VEGFR2 was extremely slow (t(1/2) >17 h), and the affinity of TAK-593 at equilibrium (K(i)*) was less than 25 pM . 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 . TAK-593 strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM .
in vivo: 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 . Oral administration of TAK-593 at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C=8%) .