Developments in Selective Small Molecule ATP-Competitive Inhibitors Targeting the Serine/Threonine Kinase Akt/PKB

摘要

The serine/threonine kinase Akt, also known as protein kinase B (PKB), plays a key role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the Phosphatidylinositol 3-kinase (PBK)/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. For these reasons, Akt is considered as an attractive target for cancer therapy. In the past few years, several series of compounds with diverse structural features have been reported as Akt inhibitors, such as, ATP-competitive inhibitors, Phosphatidylinositol (PI) analogs, and allosteric inhibitors. Although most of the inhibitors exhibited potent inhibitory activities at nanomolar concentrations against Akt, some of them have shown unfavorable selectivity against other protein kinases especially PKA and PKC. This review will focus on the recent advances in the development and biological evaluation of selective ATP-competitive inhibitors for Akt. We will summarize the novel approaches toward the developments of selective ATP-competitive inhibitors, expecting to give information to design new ATP-competitive inhibitors with high selectivity, bioavailability, and potency.