The PI3K/Akt pathway: 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 allosteric and ATP-competitive small molecule inhibitors for the serine/threonine kinase Akt (protein kinase B, PKB). Unregulated activation of the PI3K/Akt/PTEN pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers making Akt an exciting new target for cancer therapy. The development of Akt inhibitors has been complicated and hampered by the presence of three Akt isozymes, (Akt1, Akt2 and Akt3) which differ in function and tissue distribution, as well as a lack of Akt specific inhibitors. In the past 18 months, a large number of reports have appeared describing the discovery and development of allosteric Akt kinase inhibitors and classical ATP-competitive Akt kinase inhibitors. This review will discuss the PI3K/Akt/PTEN pathway, allosteric and ATP-competitive Akt kinase inhibitors, their biological evaluation and progress towards target validation.
Lindsley
Craig W
CW
VICB Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Department of Chemistry, Vanderbilt University, Nashville, TN 37232 USA. craig.lindsley@vanderbilt.edu
Barnett
Stanley F
SF
Layton
Mark E
ME
Bilodeau
Mark T
MT
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013678:Technology, Pharmaceutical / Q000639:trends
D000255:Adenosine Triphosphate; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt