TAK-593

• CAT Number: I000092
• CAS Number: 1005780-62-0
• Molecular Formula: C23H23N7O3
• Molecular Weight: 445.47
• Purity: ≥95%
• Target: VEGFR/PDGFR
• Solubility: DMSO: ≥ 48.5 mg/mL
• Storage: Store at -20°C
• IC50: 3.2/0.95/1.1 nM(VEGFR1/2/3); 4.3/1/13 nM(PDGFRα/PDGFRα V561D/PDGFRβ) [1]

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) [1]Target: VEGFR/PDGFRin 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 [1]. 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 [2]. TAK-593 strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM [3].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 [2]. 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%) [3].

Reference

1:Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor. Miyamoto N, Sakai N, Hirayama T, Miwa K, Oguro Y, Oki H, Okada K, Takagi T, Iwata H, Awazu Y, Yamasaki S, Takeuchi T, Miki H, Hori A, Imamura S.Bioorg Med Chem. 2013 Apr 15;21(8):2333-45. doi: 10.1016/j.bmc.2013.01.074. Epub 2013 Feb 13. PMID: 23498918 2: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. Awazu Y, Mizutani A, Nagase Y, Tsuchiya S, Nakamura K, Kakoi Y, Kitahara O, Takeuchi T, Yamasaki S, Miyamoto N, Iwata H, Miki H, Imamura S, Hori A.Cancer Sci. 2013 Apr;104(4):486-94. doi: 10.1111/cas.12101. Epub 2013 Feb 18. PMID: 23305239 Free Article3:Biochemical characterization of TAK-593, a novel VEGFR/PDGFR inhibitor with a two-step slow binding mechanism. Iwata H, Imamura S, Hori A, Hixon MS, Kimura H, Miki H.Biochemistry. 2011 Feb 8;50(5):738-51. doi: 10.1021/bi101777f. Epub 2011 Jan 10. PMID: 21182308