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PDBsum entry 2vnw
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References listed in PDB file
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Key reference
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Title
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Identification of 4-(4-Aminopiperidin-1-Yl)-7h-Pyrrolo[2,3-D]pyrimidines as selective inhibitors of protein kinase b through fragment elaboration.
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Authors
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J.J.Caldwell,
T.G.Davies,
A.Donald,
T.Mchardy,
M.G.Rowlands,
G.W.Aherne,
L.K.Hunter,
K.Taylor,
R.Ruddle,
F.I.Raynaud,
M.Verdonk,
P.Workman,
M.D.Garrett,
I.Collins.
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Ref.
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J Med Chem, 2008,
51,
2147-2157.
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PubMed id
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Abstract
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Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor
scaffold. Fragment elaboration using iterative crystallography of
inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the
potency and selectivity of the compounds, resulting in the identification of
nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and
4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with
antiproliferative activity and showing pathway inhibition in cells. A divergence
in the binding mode was seen between 4-aminomethylpiperidine and
4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed
with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor
(30-fold) showed significantly different bound conformations between PKA and
PKA-PKB chimera.
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