title: In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316.
abstract: 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.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.forename: Nathan
authors.initials: N
authors.lastname: Ihle
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Baker
authors.forename: Jaime M
authors.initials: JM
authors.lastname: Gard
authors.forename: Chelsea
authors.initials: C
authors.lastname: Stamper
authors.forename: Ryan
authors.initials: R
authors.lastname: Williams
authors.forename: Amy
authors.initials: A
authors.lastname: Coon
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: George
authors.forename: Lynn
authors.initials: L
authors.lastname: Kirkpatrick
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D007295:Inositol Phosphates / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D000077191:Wortmannin; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000730:Androstadienes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D000077191:Wortmannin; D047392:beta-Cyclodextrins; C435044:1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol; C494918:AKT1 protein, human