Abstract
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 (PI3K)/Akt pathway is a prominent feature of many human cancers and Akt is overexpressed 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.
Keywords: Akt, ATP-competitive inhibitors, PI3K/Akt signaling pathway, selective, Serine, Threonine, Phosphatidylinositol, allosteric inhibitors, downstream effectors, protein kinase B
Mini-Reviews in Medicinal Chemistry
Title: Developments in Selective Small Molecule ATP-Targeting the Serine/Threonine Kinase Akt/PKB
Volume: 11 Issue: 13
Author(s): P. Wang, L. Zhang, Q. Hao and G. Zhao
Affiliation:
Keywords: Akt, ATP-competitive inhibitors, PI3K/Akt signaling pathway, selective, Serine, Threonine, Phosphatidylinositol, allosteric inhibitors, downstream effectors, protein kinase B
Abstract: 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 (PI3K)/Akt pathway is a prominent feature of many human cancers and Akt is overexpressed 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.
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Cite this article as:
Wang P., Zhang L., Hao Q. and Zhao G., Developments in Selective Small Molecule ATP-Targeting the Serine/Threonine Kinase Akt/PKB, Mini-Reviews in Medicinal Chemistry 2011; 11 (13) . https://dx.doi.org/10.2174/138955711797655380
DOI https://dx.doi.org/10.2174/138955711797655380 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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