Recent progress in the discovery of Akt inhibitors as anticancer agents

Abstract

Akt, also referred to as protein kinase B (PKB) or Related to A and C (RAC), is one of the major direct downstream targets of phosphoinositide 3-kinase (PI3K). As it plays a central role in promoting cancer cell proliferation and survival through a growing list of key substrates, intense efforts are underway to find inhibitors of Akt for the treatment of cancer. Discovery of potent and novel inhibitors of Akt has been facilitated greatly by the availability of the X-ray structure of the active form of Akt and by its structural similarity with other serine/threonine kinases. In this review, new Akt inhibitors for the treatment of cancer are comprehensively reviewed, with emphasis on small molecule inhibitors that bind to the ATP-binding site, allosteric sites and the PH domains. Inhibitors of pseudosubstrates and antisense oligonucleotides, as well as Akt inhibitors with unknown mechanism of actions, are also reviewed. Results of clinical trials of several Akt drug candidates are briefly discussed. A brief summary of Akt structure and regulation and the evidences supporting Akt as a cancer target is provided as well. The patent literature is surveyed through July 2007.

Keywords::

• 1D-3-KRX-0401
• A-443654
• A-674563
• archexin
• Akt inhibitor
• azepteridine
• balanol
• Chir18-10AS
• Chir18-1AS
• doxazosin
• fingolimod
• FPA-124
• genistein
• GSK690693
• H-89
• I3C
• ISIS28903
• ISIS29208
• KP372-1
• lapatinib
• NL-71-1-1
• NSC154020
• NSC639966
• perifosine
• PKB inhibitor
• PX-316
• PX-332
• Ro-31-8220
• Ro-31-8425
• RX-0020
• RX-0194
• RX-0201
• SR13668
• triciribine
• TY-60020-57
• VQD-002
• XL418

Acknowledgments

First of all, I would like thank my wife C Zhao for her encouragement and support. I wish to express my great appreciation to a number of my colleagues for proof-reading the manuscript and providing invaluable suggestions: R Keyes, M Weitzberg, K Barr, M Fenter and Y Pan. I am also greatly indebted to K Li and E Li for their help in proofreading the manuscript.

This paper is dedicated to Professor P Zhang of Beijing University on the occasion of his 90th birthday.

Notes