Synthesis and evaluation of indazole based analog sensitive Akt inhibitors
Tatsuya Okuzumi1, Gregory S Ducker, Chao Zhang
1Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, MC 2280, San Francisco, California 94158, USA.
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-substituted version of the Abbott Labs Akt inhibitor A-443654.
Insights
Researchers developed a novel chemical genetics strategy using an analog-sensitive Akt kinase mutant and a selective inhibitor, PrINZ, to study Akt signaling pathways and overcome paradoxical hyperphosphorylation observed with traditional Akt inhibitors.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- The Akt kinase is crucial for cell growth and survival, making it a significant target in cancer drug development.
- Aberrant PI3K/Akt signaling is frequently observed in various cancers.
- Akt inhibitors paradoxically can cause hyperphosphorylation of Akt itself, complicating therapeutic strategies.
Purpose of the Study:
- To investigate the paradoxical hyperphosphorylation of Akt induced by active site inhibitors.
- To develop a selective chemical genetics approach for studying Akt signaling.
- To create a tool compound for precise Akt inhibition.
Main Methods:
- Utilized a chemical genetics strategy to engineer an analog-sensitive Akt mutant.
- Introduced an active site substitution in Akt to enable selective inhibitor binding.
- Synthesized a novel inhibitor, PrINZ, specifically targeting the analog-sensitive Akt mutant.
Main Results:
- Successfully generated an analog-sensitive Akt kinase mutant.
- Developed PrINZ, a selective inhibitor for the engineered Akt mutant.
- This strategy allows for precise control over Akt activity.
Conclusions:
- The analog-sensitive Akt strategy provides a powerful tool to dissect Akt signaling pathways.
- This approach can overcome limitations of conventional Akt inhibitors, such as paradoxical hyperphosphorylation.
- Further research into Akt signaling and targeted inhibition is warranted for cancer therapy.
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