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PDBsum entry 3vo3
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Transferase/transferase inhibitor
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PDB id
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3vo3
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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N.Miyamoto,
N.Sakai,
T.Hirayama,
K.Miwa,
Y.Oguro,
H.Oki,
K.Okada,
T.Takagi,
H.Iwata,
Y.Awazu,
S.Yamasaki,
T.Takeuchi,
H.Miki,
A.Hori,
S.Imamura.
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Ref.
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Bioorg Med Chem Lett, 2013,
21,
2333-2345.
[DOI no: ]
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PubMed id
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Abstract
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Vascular endothelial growth factor (VEGF) plays important roles in tumor
angiogenesis, and the inhibition of its signaling pathway is considered an
effective therapeutic option for the treatment of cancer. In this study, we
describe the design, synthesis, and biological evaluation of
2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two
distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the
discovery of
N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide
(23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC50
value of 0.95 nM. The compound 23a strongly suppressed proliferation of
VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM.
Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth
factor receptor kinases as well as VEGF receptor kinases. Oral administration of
23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model
using human lung adenocarcinoma A549 cells (T/C=8%).
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