The development of phosphatidylinositol ether lipid analogues as inhibitors of the serine/threonine kinase, Akt.
The serine/threonine kinase Akt is a component of the phosphatidylinositol 3'-kinase/Akt signal transduction pathway that is activated by receptor tyrosine kinases, activated Ras and integrins. As Akt regulates many processes crucial to carcinogenesis, and Akt activation has been observed in human cancers, intense efforts are underway to develop Akt inhibitors as cancer therapeutics. Towards this aim, phosphatidylinositol ether lipid analogues (PIAs), which are structurally similar to the products of phosphatidylinositol 3'-kinase, have been synthesised. PIAs inhibit Akt translocation, phosphorylation and kinase activity. Furthermore, they selectively induce apoptosis in cancer cell lines that depend on Akt for survival. This review will trace the development of PIAs, cover the biological activities of PIAs and discuss future steps and challenges in their development.
Gills
Joell J
JJ
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, USA.
Dennis
Phillip A
PA
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010716:Phosphatidylinositols / Q000494:pharmacology*; D010742:Phospholipid Ethers / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt
D004791:Enzyme Inhibitors; D010716:Phosphatidylinositols; D010742:Phospholipid Ethers; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt