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PDBsum entry 5eyd
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Transferase/transferase inhibitor
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PDB id
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5eyd
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PDB id:
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Transferase/transferase inhibitor
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Title:
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Crystal structure of c-met in complex with amg 337
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: residues 1048-1351. 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: trichoplusia ni. Expression_system_taxid: 7111.
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Resolution:
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1.85Å
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R-factor:
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0.196
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R-free:
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0.249
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Authors:
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D.A.Whittington,A.M.Long
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Key ref:
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A.A.Boezio
et al.
(2016).
Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.
J Med Chem,
59,
2328-2342.
PubMed id:
DOI:
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Date:
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24-Nov-15
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Release date:
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10-Feb-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.
289 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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J Med Chem
59:2328-2342
(2016)
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PubMed id:
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Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.
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A.A.Boezio,
K.W.Copeland,
K.Rex,
B.K Albrecht,
D.Bauer,
S.F.Bellon,
C.Boezio,
M.A.Broome,
D.Choquette,
A.Coxon,
I.Dussault,
S.Hirai,
R.Lewis,
M.H.Lin,
J.Lohman,
J.Liu,
E.A.Peterson,
M.Potashman,
R.Shimanovich,
Y.Teffera,
D.A.Whittington,
K.R.Vaida,
J.C.Harmange.
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ABSTRACT
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Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition
factor (MET) has been implicated in several human cancers and is an attractive
target for small molecule drug discovery. Herein, we report the discovery of
compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase
activity, desirable preclinical pharmacokinetics, significant inhibition of MET
phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent
mouse efficacy model.
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