Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors

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Abstract

This letter describes the development of two series of potent and selective allosteric Akt kinase inhibitors that display an unprecedented level of selectivity for either Akt1, Akt2 or both Akt1/Akt2. An iterative analog library synthesis approach quickly provided a highly selective Akt1/Akt2 inhibitor that induces apoptosis in tumor cells and inhibits Akt phosphorylation in vivo.

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Acknowledgements

The authors wish to thank Dr. Charles W. Ross III for obtaining HRMS data and Dr. Sandor Varga for NMR work to identify and characterize the regioisomeric quinoxalines and pyrazinones.

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