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Issue 8, 2010
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Synthesis and evaluation of indazole based analog sensitive Akt inhibitors

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Abstract

The kinase Akt is a key signaling node in regulating cellular growth and survival. It is implicated in cancer by mutation and its role in the downstream transmission of aberrant PI3K signaling. For these reasons, Akt has become an increasingly important target of drug development efforts and several inhibitors are now reaching clinical trials. Paradoxically it has been observed that active site kinase inhibitors of Akt lead to hyperphosphorylation of Akt itself. To investigate this phenomenon we here describe the application of a chemical genetics strategy that replaces native Akt with a mutant version containing an active site substitution that allows for the binding of an engineered inhibitor. This analog sensitive strategy allows for the selective inhibition of a single kinase. In order to create the inhibitor selective for the analog sensitive kinase, a diversity of synthetic approaches was required, finally resulting in the compound PrINZ, a 7-substiututed version of the Abbott Labs Akt inhibitor A-443654.

Graphical abstract: Synthesis and evaluation of indazole based analog sensitive Akt inhibitors

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Supplementary files

Article information


Submitted
05 Mar 2010
Accepted
19 Apr 2010
First published
28 Jun 2010

Mol. BioSyst., 2010,6, 1389-1402
Article type
Paper

Synthesis and evaluation of indazole based analog sensitive Akt inhibitors

T. Okuzumi, G. S. Ducker, C. Zhang, B. Aizenstein, R. Hoffman and K. M. Shokat, Mol. BioSyst., 2010, 6, 1389
DOI: 10.1039/C003917A

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