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PDBsum entry 3vw8
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Transferase/transferase inhibitor
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PDB id
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3vw8
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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 human c-met kinase domain with its inhibitor
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: unp residues 1024-1352. Synonym: hgf receptor, hgf/sf receptor, proto-oncogenE C-met, scatter factor receptor, sf receptor, tyrosine-protein kinase met. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: met. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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2.10Å
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R-factor:
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0.215
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R-free:
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0.259
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Authors:
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S.Matsumoto,N.Miyamoto,T.Hirayama,H.Oki,K.Okada,M.Tawada,H.Iwata, H.Miki,K.Nakamura,A.Hori,S.Imamura
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Key ref:
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S.Matsumoto
et al.
(2013).
Structure-based design, synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors.
Bioorg Med Chem Lett,
21,
7686-7698.
PubMed id:
DOI:
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Date:
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08-Aug-12
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Release date:
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14-Aug-13
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PROCHECK
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Headers
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References
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P08581
(MET_HUMAN) -
Hepatocyte growth factor receptor from Homo sapiens
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Seq:
Struc:
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1390 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
21:7686-7698
(2013)
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PubMed id:
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Structure-based design, synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors.
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S.Matsumoto,
N.Miyamoto,
T.Hirayama,
H.Oki,
K.Okada,
M.Tawada,
H.Iwata,
K.Nakamura,
S.Yamasaki,
H.Miki,
A.Hori,
S.Imamura.
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ABSTRACT
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To identify compounds with potent antitumor efficacy for various human cancers,
we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial
transition factor (c-Met) and vascular endothelial growth factor receptor 2
(VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal
structural information from c-Met and VEGFR2 in complex with known inhibitors.
This led to the identification of compounds 3a and 3b, which were capable of
suppressing both c-Met and VEGFR2 kinase activities. Further optimization
resulted in pyrazolone and pyridone derivatives, which could form intramolecular
hydrogen bonds to enforce a rigid conformation, thereby producing potent
inhibition. One compound of particular note was the imidazo[1,2-a]pyridine
derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both
c-Met and VEGFR2 enzyme activities (IC50=1.9, 2.2nM), as well as proliferation
of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein
endothelial cells (IC50=5.0, 1.8nM). Compound 26 exhibited dose-dependent
antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C]=4%, po, 5mg/kg,
once-daily) and COLO205 (T/C=13%, po, 15mg/kg, once-daily) mouse xenograft
models.
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