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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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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Crystal structure of the kinase domain of human vegfr2 with imidazo[1, 2-b]pyridazine derivative
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Structure:
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Vascular endothelial growth factor receptor 2. Chain: a. Fragment: unp residues 806-1171. Synonym: vegfr-2, fetal liver kinase 1, flk-1, kinase insert domain receptor, kdr, protein-tyrosine kinase receptor flk-1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1, vegfr2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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1.52Å
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R-factor:
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0.162
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R-free:
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0.182
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Authors:
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H.Oki,K.Okada
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Key ref:
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N.Miyamoto
et al.
(2013).
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.
Bioorg Med Chem Lett,
21,
2333-2345.
PubMed id:
DOI:
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Date:
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19-Jan-12
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Release date:
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06-Mar-13
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PROCHECK
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Headers
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References
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P35968
(VGFR2_HUMAN) -
Vascular endothelial growth factor receptor 2 from Homo sapiens
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Seq:
Struc:
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1356 a.a.
303 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
21:2333-2345
(2013)
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PubMed id:
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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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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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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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