Preferential inhibition of Akt and killing of Akt-dependent cancer cells by rationally designed phosphatidylinositol ether lipid analogues

Cancer Res. 2004 Apr 15;64(8):2782-92. doi: 10.1158/0008-5472.can-03-1530.


Activation of the PI3k/Akt pathway controls key cellular processes and contributes to tumorigenesis in vivo, but investigation of the PI3k/Akt pathway has been limited by the lack of specific inhibitors directed against Akt. To develop Akt inhibitors, we used molecular modeling of the pleckstrin homology (PH) domain of Akt to guide synthesis of structurally modified phosphatidylinositol ether lipid analogues (PIAs). Here, we characterize the biochemical and cellular effects of PIAs. Of 24 compounds tested, five PIAs with modifications at two sites on the inositol ring inhibited Akt with IC(50)s < 5 micro M. Molecular modeling identified putative interactions of PIAs with the phosphoinositide-binding site in the PH domain of Akt, and growth factor-induced translocation of Akt to the plasma membrane was inhibited by PIA administration. Inhibition of Akt occurred rapidly and was maintained for hours. PIAs decreased phosphorylation of many downstream targets of Akt without affecting upstream kinases, such as PI3k or phosphoinositide-dependent kinase-1, or members of other kinase pathways such as extracellular signal-regulated kinase. Importantly, PIAs increased apoptosis 20-30-fold in cancer cell lines with high levels of endogenous Akt activity but only 4-5-fold in cancer cell lines with low levels of Akt activity. These studies identify PIAs as effective Akt inhibitors, and provide proof of principle for targeting the PH domain of Akt.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen-Ion Concentration
  • Insulin-Like Growth Factor I / pharmacology
  • Kinetics
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Models, Molecular
  • Phosphatidylinositols / pharmacology*
  • Phospholipid Ethers / pharmacology*
  • Protein Serine-Threonine Kinases*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Structure-Activity Relationship
  • Substrate Specificity
  • Transfection


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Phosphatidylinositols
  • Phospholipid Ethers
  • Proto-Oncogene Proteins
  • Insulin-Like Growth Factor I
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt