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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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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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J Med Chem, 2013,
56,
2294-2310.
[DOI no: ]
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PubMed id
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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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