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PDBsum entry 4mxc
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Transferase/transferase inhibitor
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PDB id
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4mxc
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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 cmet in complex with novel inhibitor
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: protein kinase domain, unp resodies 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: cmet, met. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.63Å
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R-factor:
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0.181
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R-free:
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0.208
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Authors:
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Q.F.Liu,T.T.Chen,Y.C.Xu
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Key ref:
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Z.Zhan
et al.
(2014).
Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity.
Acs Med Chem Lett,
5,
673-678.
PubMed id:
DOI:
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Date:
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26-Sep-13
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Release date:
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15-Oct-14
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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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Acs Med Chem Lett
5:673-678
(2014)
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PubMed id:
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Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity.
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Z.Zhan,
J.Ai,
Q.Liu,
Y.Ji,
T.Chen,
Y.Xu,
M.Geng,
W.Duan.
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ABSTRACT
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Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we
report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an
anilinopyrimidine scaffold. Two novel synthetic protocols were employed for
rapid analoguing of the designed molecules for structure-activity relationship
(SAR) exploration. Some analogues displayed nanomolar potency against c-Met and
VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a
exhibited potent antiproliferative effect against c-Met addictive cell lines
with IC50 values ranged from 0.33 to 1.7 μM. In addition, a cocrystal structure
of c-Met in complex with 3h has been determined, which reveals the binding mode
of c-Met to its inhibitor and helps to interpret the SAR of the analogues.
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Links
