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PDBsum entry 3mvj
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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 of selective, Atp-Competitive inhibitors of akt.
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Authors
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K.D.Freeman-Cook,
C.Autry,
G.Borzillo,
D.Gordon,
E.Barbacci-Tobin,
V.Bernardo,
D.Briere,
T.Clark,
M.Corbett,
J.Jakubczak,
S.Kakar,
E.Knauth,
B.Lippa,
M.J.Luzzio,
M.Mansour,
G.Martinelli,
M.Marx,
K.Nelson,
J.Pandit,
F.Rajamohan,
S.Robinson,
C.Subramanyam,
L.Wei,
M.Wythes,
J.Morris.
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Ref.
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J Med Chem, 2010,
53,
4615-4622.
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PubMed id
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Abstract
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This paper describes the design and synthesis of novel, ATP-competitive Akt
inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include
the discovery of an initial lead that was modestly selective and medicinal
chemistry optimization of that lead to provide more selective analogues.
Analysis of the data suggested that highly lipophilic analogues would likely
suffer from poor overall properties. Central to the discussion is the concept of
optimization of lipophilic efficiency and the ability to balance overall
druglike propeties with the careful control of lipophilicity in the lead series.
Discovery of the nonracemic amide series and subsequent modification produced an
advanced analogue that performed well in advanced preclinical assays, including
xenograft tumor growth inhibition studies, and this analogue was nominated for
clinical development.
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