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PDBsum entry 4xyf
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Transferase/transferase inhibitor
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PDB id
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4xyf
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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 c-met in complex with (s)-5-(8-fluoro-3-(1-(3-(2- methoxyethoxy)quinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6- yl)-3-methylisoxazole
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: kinase domain (unp 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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0.188
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R-free:
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0.236
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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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E.A.Peterson
et al.
(2015).
Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
J Med Chem,
58,
2417-2430.
PubMed id:
DOI:
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Date:
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02-Feb-15
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Release date:
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11-Mar-15
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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.
290 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
58:2417-2430
(2015)
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PubMed id:
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Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
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E.A.Peterson,
Y.Teffera,
B.K.Albrecht,
D.Bauer,
S.F.Bellon,
A.Boezio,
C.Boezio,
M.A.Broome,
D.Choquette,
K.W.Copeland,
I.Dussault,
R.Lewis,
M.H.Lin,
J.Lohman,
J.Liu,
M.Potashman,
K.Rex,
R.Shimanovich,
D.A.Whittington,
K.R.Vaida,
J.C.Harmange.
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ABSTRACT
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The overexpression of c-Met and/or hepatocyte growth factor (HGF), the
amplification of the MET gene, and mutations in the c-Met kinase domain can
activate signaling pathways that contribute to cancer progression by enabling
tumor cell proliferation, survival, invasion, and metastasis. Herein, we report
the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity.
Optimization of the 8-fluorotriazolopyridine scaffold through the combination of
structure-based drug design, SAR studies, and metabolite identification provided
potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable
pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated
c-Met phosphorylation in a mouse liver pharmacodynamic model.
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Links
