Specific inhibition of the akt1 pleckstrin homology domain by D-3-deoxy-phosphatidyl-myo-inositol analogues

Emmanuelle Meuillet, Daruka Mahadevan, Hariprasad Vankayalapati, Margareta Berggren, Ryan Williams, Amy Coon, Alan P. Kozikowski, Garth Powis

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78 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)389-399
Number of pages11
JournalMolecular Cancer Therapeutics
Volume2
Issue number4
Publication statusPublished - Apr 2003

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Meuillet, E., Mahadevan, D., Vankayalapati, H., Berggren, M., Williams, R., Coon, A., ... Powis, G. (2003). Specific inhibition of the akt1 pleckstrin homology domain by D-3-deoxy-phosphatidyl-myo-inositol analogues. Molecular Cancer Therapeutics, 2(4), 389-399.