In Vivo Molecular Pharmacology and Antitumor Activity of the Targeted Akt Inhibitor PX-316

Authors: Emmanuelle J. Meuillet¹; Nathan Ihle¹; Amanda F. Baker¹; Jaime M. Gard¹; Chelsea Stamper¹; Ryan Williams¹; Amy Coon¹; Daruka Mahadevan¹; Benjamin L. George¹; Lynn Kirkpatrick²; Garth Powis¹

Source: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, Volume 14, Number 10, 2004 , pp. 513-527(15)

Publisher: Cognizant Communication Corporation

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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-3 bgr

, 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- bgr

-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.

Keywords: PX-316; d-3-Deoxy-phosphatidyl-myo-inositol ether lipid; Akt; Antitumor activity; Pharmacodynamics

Document Type: Research article

Affiliations: 1: *Arizona Cancer Center, University of Arizona, Tucson, AZ 85724 2: †ProlX Pharmaceuticals, Tucson, AZ 85701

Publication date: 2004-01-01

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Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.

In Vivo Molecular Pharmacology and Antitumor Activity of the Targeted Akt Inhibitor PX-316

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