Synthesis and evaluation of indazole based analog sensitive Akt inhibitors
| Autor: | Tatsuya Okuzumi, Kevan M. Shokat, Randy Hoffman, Brian Aizenstein, Gregory S. Ducker, Chao Zhang |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Indazoles Indoles Kinase Cell growth Akt/PKB signaling pathway Drug Evaluation Preclinical Hyperphosphorylation Biology Pharmacology Models Biological Article Substrate Specificity Cell biology Drug development Humans Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt Molecular Biology Chemical genetics Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Biotechnology |
| Zdroj: | Molecular BioSystems. 6:1389 |
| ISSN: | 1742-2051 1742-206X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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