Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors

This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. Recently, several series of small molecule, ATP-competitive inhibitors have been reported with a range of Akt potencies and selectivities. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other pleckstrin homology (PH) domain containing proteins and may have poor bioavailability. In addition, novel allosteric inhibitors have been reported which are PH domain dependent, exhibit selectivity for the individual Akt isozymes and inhibit the activity and the activation of Akt. Compounds within these classes Akt inhibitors have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.