Specific inhibition of the Akt1 pleckstrin homology domain by D-3-deoxy-phosphatidyl-myo-inositol analogues.

Abstract	Activation of Akt (protein kinase B), a Ser/Thr protein kinase that promotes cell survival, has been linked to tumorigenesis. Akt is activated by phosphorylation after binding of its pleckstrin homology (PH) domain to plasma membrane phosphatidyl-myo-inositol-3-phosphates, formed by phosphoinositide-3-kinase. We report a novel strategy to inhibit Akt activation based on the use of D-3-deoxy-phosphatidyl-myo-inositols (DPIs) that cannot be phosphorylated on the 3-position of the myo-inositol ring. We have studied the DPIs, DPI 1-[(R)-2,3-bis(hexadecanoyloxy)propyl hydrogen phosphate], its ether lipid derivative DPI 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (DPIEL), and its carbonate derivative DPI 1-[(R)-2-methoxy-3-octadecyloxypropyl carbonate]. We demonstrate in platelet-derived growth factor-stimulated mouse NIH3T3 cells that the DPIs bind to the PH domain of Akt, trapping it in the cytoplasm and thus preventing Akt activation. DPIEL did not inhibit myristylated-Akt, a constitutively active membrane-bound Akt expressed in NIH3T3 cells, and cell growth was not inhibited, unlike in wild-type NIH3T3 cells. Molecular modeling and docking studies show that DPIEL binds with much higher affinity to Akt's PH domain as compared with DPI and DPI 1-[(R)-2-methoxy-3-octadecyloxypropyl carbonate]. This study shows that the DPIs are a novel class of growth inhibitory agents with a novel mechanism of action through binding to the PH domain of Akt and inhibition of Akt activation.
Authors	Emmanuelle J Meuillet, Daruka Mahadevan, Hariprasad Vankayalapati, Margareta Berggren, Ryan Williams, Amy Coon, Alan P Kozikowski, Garth Powis
Journal	Molecular cancer therapeutics (Mol Cancer Ther) Vol. 2 Issue 4 Pg. 389-99 (Apr 2003) ISSN: 1535-7163 [Print] United States
PMID	12700283 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Blood Proteins Enzyme Inhibitors Myristic Acids Phosphatidylinositols Phosphoproteins Proto-Oncogene Proteins platelet protein P47 Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt
Topics	Animals Apoptosis Binding Sites Blood Proteins (chemistry) Cell Division Cell Line, Tumor Cell Membrane (metabolism) Dose-Response Relationship, Drug Enzyme Activation Enzyme Inhibitors (pharmacology) Lipid Metabolism Mice Models, Biological Models, Chemical Models, Molecular Myristic Acids (metabolism) NIH 3T3 Cells Phosphatidylinositol 3-Kinases (metabolism) Phosphatidylinositols (chemistry, pharmacology) Phosphoproteins (chemistry) Phosphorylation Protein Binding Protein Serine-Threonine Kinases (antagonists & inhibitors, chemistry) Protein Structure, Tertiary Protein Transport Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Transfection

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