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PDBsum entry 2f7z
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References listed in PDB file
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Key reference
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Title
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Synthesis and structure-Activity relationship of 3,4'-Bispyridinylethylenes: discovery of a potent 3-Isoquinolinylpyridine inhibitor of protein kinase b (pkb/akt) for the treatment of cancer.
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Authors
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Q.Li,
K.W.Woods,
S.Thomas,
G.D.Zhu,
G.Packard,
J.Fisher,
T.Li,
J.Gong,
J.Dinges,
X.Song,
J.Abrams,
Y.Luo,
E.F.Johnson,
Y.Shi,
X.Liu,
V.Klinghofer,
R.Des jong,
T.Oltersdorf,
V.S.Stoll,
C.G.Jakob,
S.H.Rosenberg,
V.L.Giranda.
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Ref.
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Bioorg Med Chem Lett, 2006,
16,
2000-2007.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led
to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor
with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity
against distinct families of kinases such as tyrosine kinases and CAMK, and
displays poor to marginal selectivity against closely related kinases in the AGC
and CMGC families. Moreover, 13a demonstrates potent cellular activity
comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against
MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of
phosphorylation of the Akt downstream target GSK3 was also observed in
FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and
13a in complex with PKA in the ATP-binding site were determined.
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