Novel PI analogues selectively block activation of the pro-survival serine/threonine kinase Akt

J Am Chem Soc. 2003 Feb 5;125(5):1144-5. doi: 10.1021/ja0285159.


The synthesis from l-quebrachitol of a series of 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation of Akt and downstream substrates without affecting activation of the upstream kinase, PDK-1, or other kinases downstream of ras such as MAPK in H157 and H1703 lung cancer cells that have high levels of constitutively active Akt. The 2-hydroxyl in these compounds was deleted or alkylated with the intent to preclude metabolic degradation of these compounds by PI-specific phospholipase C (PI-PLC). PI analogues with phosphate linkers are more effective than those with carbonate linkers. Specific inhibition of Akt by these compounds validates ligand design targeted to the PH domains of crucial signaling proteins, thus providing a unique class of possible cancer therapeutics.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Lung Neoplasms / enzymology
  • Phosphatidylinositols / chemical synthesis
  • Phosphatidylinositols / pharmacology*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Tumor Cells, Cultured


  • Enzyme Inhibitors
  • Phosphatidylinositols
  • Proto-Oncogene Proteins
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt