In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316

Oncol Res. 2004;14(10):513-27. doi: 10.3727/0965040042380487.


Akt, a serine/threonine kinase that promotes cell survival, is activated by binding of its pleckstrin homology (PH) domain to membrane phosphatidylinositol (PtdIns)-3-phosphates formed by PtdIns-3-kinase. D-3-Deoxy-phosphatidyl-myo-inositols that cannot be phosphorylated on the 3-position of the myo-inositol group are inhibitors of the Akt PH domain. The most active compound is D-3-deoxy-phosphatidyl-myo-inositol 1-[(R)-2-methoxy-3-octadecyloxypropyl hydrogen phosphate] (PX-316). PX-316 administered intraperitoneally to mice at 150 mg/kg inhibits Akt activation in HT-29 human tumor xenografts up to 78% at 10 h with recovery to 34% at 48 h. Phosphorylation of GSK-3beta, a downstream target of Akt, is also inhibited. There is no decrease in PtdIns(3,4,5)-trisphosphate levels by PX-316, showing it is not an inhibitor of PtdIns-3-K in vivo. Gene expression profiling of HT-29 tumor xenografts shows many similarities between the effects of PX-316 and the PtdIns-3-K inhibitor wortmannin, with downregulation of several ribosomal-related genes, while PX-316 uniquely increases the expression of a group of mitochondrial-related genes. PX-316 has antitumor activity against early human MCF-7 breast cancer and HT-29 colon cancer xenografts in mice. PX-316 formulated in 20% hydroxypropyl-beta-cyclodextrin for intravenous administration is well tolerated in mice and rats with no hemolysis and no hematological toxicity. Thus, PX-316 is the lead compound of a new class of potential agents that inhibit Akt survival signaling.

Publication types

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

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Androstadienes / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Inhibitory Concentration 50
  • Inositol Phosphates / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Mitochondria / metabolism
  • Models, Chemical
  • Models, Molecular
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Serine / chemistry
  • Signal Transduction
  • Time Factors
  • Wortmannin
  • beta-Cyclodextrins / chemistry


  • 1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol
  • Androstadienes
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Inositol Phosphates
  • Proto-Oncogene Proteins
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Serine
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Wortmannin