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PDBsum entry 5eob
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PDB id:
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Transferase
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Title:
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Crystal structure of cmet in complex with novel inhibitor
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: unp residues 1038-1346. 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: escherichia coli bl21(de3). Expression_system_taxid: 469008.
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Resolution:
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1.75Å
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R-factor:
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0.174
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R-free:
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0.197
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Authors:
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Q.Liu,T.Chen,Y.Xu
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Key ref:
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Z.Zhan
et al.
(2016).
Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor.
Eur J Med Chem,
116,
239-251.
PubMed id:
DOI:
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Date:
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10-Nov-15
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Release date:
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19-Oct-16
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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.
288 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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Eur J Med Chem
116:239-251
(2016)
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PubMed id:
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Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor.
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Z.Zhan,
X.Peng,
Q.Liu,
F.Chen,
Y.Ji,
S.Yao,
Y.Xi,
Y.Lin,
T.Chen,
Y.Xu,
J.Ai,
M.Geng,
W.Duan.
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ABSTRACT
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c-Met/HGF overexpression has been detected in many human malignancies including
tumors which are resistant to anticancer therapy. Disrupting the aberrant
c-Met/HGF axis has enjoyed significant progress in both preclinical and clinical
antitumor campaign. To eliminate the OCH2-related metabolic deficiency of our
previously reported triazolotriazine 2, we synthesized a series of
CH2-/CF2-linked triazolotriazines and assessed their c-Met activities, leading
to the highly potent compound 23 with IC50 values of 0.24 nM of enzymatic
activity in c-Met and 0.85 nM of cellular activity in EBC-1 cancer cell line,
as well as with complete tumor regression in EBC-1 xenograft mice model at dose
of 25 mg/kg via oral administration. Based on its potent anti-proliferative
activities and favorable pharmacokinetic properties, 23 has been selected as a
drug candidate for preclinical investigation.
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