Abstract
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 chemotherapy and it has been postulated that inhibition of Akt alone or in combination with standard cancer chemotherapeutics will 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. The majority of small molecule inhibitors in this nascent field are classic ATP-competitive inhibitors which provide little specificity. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other PH domain containing proteins and may have poor bioavailability. None of the inhibitors in these classes have been reported to have Akt isozyme specificity. Recently, novel allosteric inhibitors have been reported which are pleckstrin homology domain dependent and exhibit Akt isozyme selectivity. Inhibitors in this class may have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.
Keywords: akt. Pkb, cancer, chemotherapy, apoptosis, allosteric, inhibitors, kinase
Current Topics in Medicinal Chemistry
Title: The Akt/PKB Family of Protein Kinases: A Review of Small Molecule Inhibitors and Progress Towards Target Validation
Volume: 5 Issue: 2
Author(s): Stanley F. Barnett, Mark T. Bilodeau and Craig W. Lindsley
Affiliation:
Keywords: akt. Pkb, cancer, chemotherapy, apoptosis, allosteric, inhibitors, kinase
Abstract: 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 chemotherapy and it has been postulated that inhibition of Akt alone or in combination with standard cancer chemotherapeutics will 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. The majority of small molecule inhibitors in this nascent field are classic ATP-competitive inhibitors which provide little specificity. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other PH domain containing proteins and may have poor bioavailability. None of the inhibitors in these classes have been reported to have Akt isozyme specificity. Recently, novel allosteric inhibitors have been reported which are pleckstrin homology domain dependent and exhibit Akt isozyme selectivity. Inhibitors in this class may have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.
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Cite this article as:
Barnett F. Stanley, Bilodeau T. Mark and Lindsley W. Craig, The Akt/PKB Family of Protein Kinases: A Review of Small Molecule Inhibitors and Progress Towards Target Validation, Current Topics in Medicinal Chemistry 2005; 5 (2) . https://dx.doi.org/10.2174/1568026053507714
DOI https://dx.doi.org/10.2174/1568026053507714 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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