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PDBsum entry 4iwd
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Transferase/transferase inhibitor
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PDB id
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4iwd
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PDB id:
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Transferase/transferase inhibitor
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Title:
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Structure of dually phosphorylated c-met receptor kinase in complex with an mk-8033 analog
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Structure:
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Hepatocyte growth factor receptor. Chain: a. Fragment: unp residues 1048-1348. 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
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Resolution:
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1.99Å
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R-factor:
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0.207
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R-free:
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0.257
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Authors:
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S.M.Soisson,A.Northrup,K.Rickert,S.Patel,T.Allison
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Key ref:
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A.B.Northrup
et al.
(2013).
Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met.
J Med Chem,
56,
2294-2310.
PubMed id:
DOI:
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Date:
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23-Jan-13
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Release date:
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11-Dec-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.
302 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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*
PDB and UniProt seqs differ
at 4 residue positions (black
crosses)
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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
56:2294-2310
(2013)
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PubMed id:
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Discovery of 1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(pyridin-2-ylmethyl)methanesulfonamide (MK-8033): A Specific c-Met/Ron dual kinase inhibitor with preferential affinity for the activated state of c-Met.
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A.B.Northrup,
M.H.Katcher,
M.D.Altman,
M.Chenard,
M.H.Daniels,
S.V.Deshmukh,
D.Falcone,
D.J.Guerin,
H.Hatch,
C.Li,
W.Lu,
B.Lutterbach,
T.J.Allison,
S.B.Patel,
J.F.Reilly,
M.Reutershan,
K.W.Rickert,
C.Rosenstein,
S.M.Soisson,
A.A.Szewczak,
D.Walker,
K.Wilson,
J.R.Young,
B.S.Pan,
C.J.Dinsmore.
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ABSTRACT
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This report documents the first example of a specific inhibitor of protein
kinases with preferential binding to the activated kinase conformation:
5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron
inhibitor under investigation as a treatment for cancer. The design of 11r was
based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by
members of this structural class. A novel two-step protocol for the synthesis of
benzylic sulfonamides was developed to access 11r and analogues. We provide a
rationale for the observed selectivity based on X-ray crystallographic evidence
and discuss selectivity trends with additional examples. Importantly, 11r
provides full inhibition of tumor growth in a c-Met amplified (GTL-16)
subcutaneous tumor xenograft model and may have an advantage over inactive form
kinase inhibitors due to equal potency against a panel of oncogenic activating
mutations of c-Met in contrast to c-Met inhibitors without preferential binding
to the active kinase conformation.
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