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PDBsum entry 3efk
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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And biological evaluation of potent c-Met inhibitors.
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Authors
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N.D.D'Angelo,
S.F.Bellon,
S.K.Booker,
Y.Cheng,
A.Coxon,
C.Dominguez,
I.Fellows,
D.Hoffman,
R.Hungate,
P.Kaplan-Lefko,
M.R.Lee,
C.Li,
L.Liu,
E.Rainbeau,
P.J.Reider,
K.Rex,
A.Siegmund,
Y.Sun,
A.S.Tasker,
N.Xi,
S.Xu,
Y.Yang,
Y.Zhang,
T.L.Burgess,
I.Dussault,
T.S.Kim.
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Ref.
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J Med Chem, 2008,
51,
5766-5779.
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PubMed id
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Abstract
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c-Met is a receptor tyrosine kinase that plays a key role in several cellular
processes but has also been found to be overexpressed and mutated in different
human cancers. Consequently, targeting this enzyme has become an area of intense
research in drug discovery. Our studies began with the design and synthesis of
novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent
SAR studies identified 22 as a more potent analog, whereas an X-ray crystal
structure of 7 bound to c-Met revealed an unexpected binding conformation. This
latter finding led to the development of a new series that featured compounds
that were more potent both in vitro and in vivo than 22 and also exhibited
different binding conformations to c-Met. Novel c-Met inhibitors have been
designed, developed, and found to be potent in vitro and in vivo.
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