 |
PDBsum entry 2x39
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Discovery of 4-Amino-1-(7h-Pyrrolo[2,3-D]pyrimidin-4-Yl)piperidine-4-Carboxamides as selective, Orally active inhibitors of protein kinase b (akt).
|
|
|
Authors
|
|
T.Mchardy,
J.J.Caldwell,
K.M.Cheung,
L.J.Hunter,
K.Taylor,
M.Rowlands,
R.Ruddle,
A.Henley,
A.De haven brandon,
M.Valenti,
T.G.Davies,
L.Fazal,
L.Seavers,
F.I.Raynaud,
S.A.Eccles,
G.W.Aherne,
M.D.Garrett,
I.Collins.
|
|
|
Ref.
|
|
J Med Chem, 2010,
53,
2239-2249.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Protein kinase B (PKB or Akt) is an important component of intracellular
signaling pathways regulating growth and survival. Signaling through PKB is
frequently deregulated in cancer, and inhibitors of PKB therefore have potential
as antitumor agents. The optimization of lipophilic substitution within a series
of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided
ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for
inhibition of PKB over the closely related kinase PKA. Although active in
cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent
metabolism in vivo, leading to rapid clearance and low oral bioavailability.
Variation of the linker group between the piperidine and the lipophilic
substituent identified
4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent
and orally bioavailable inhibitors of PKB. Representative compounds modulated
biomarkers of signaling through PKB in vivo and strongly inhibited the growth of
human tumor xenografts in nude mice at well-tolerated doses.
|
|
|
|
|
|
|
