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Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling

Ihle, NT and Williams, R and Chow, S and Chew, W and Berggren, MI and Paine-Mrrieta, G and Minion, DJ and Halter, RJ and Wipf, P and Abraham, R and Kirkpatrick, L and Powis, G (2004) Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Molecular Cancer Therapeutics, 3 (7). 763 - 772. ISSN 1535-7163

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Abstract

We have developed biologically stable semisynthetic viridins as inhibitors of phosphoinositide (Ptdins)-3-kinases. The most active compound was PX-866 (acetic acid (1S, 4E, 10R, 11R, 13S, 14R -[4-diallylaminomethylene-6-hydroxy-1-methoxymethyl-10,13-dimethyl-3,7, 17-trioxo-1, 3,4,7,10,11,12,13,14,15,16,17-dodecahydro-2-oxacyclopenta [a]phenanthren-11-yl ester), which inhibited purified Ptdins-3-kinase with an IC50 of 0.1 nmol/L and Ptdins-3-kinase signaling measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells with an IC50 of 20 nmol/L. PX-866 administered to mice at 10 mg/kg inhibited phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking >48 hours after p.o. administration but more rapidly after i.v. or i.p. administration. PX-866 was eliminated from mouse plasma with a half-life of 18 minutes and a clearance of 360 mL/min/kg following i.v. administration and, when administered i.p. or p.o., showed first-pass metabolism with sequential N-deallylation. Synthetic standards of the N-deallylated metabolites of PX-866 inhibited Ptdins-3-kinase at low nanomolar per liter concentrations. PX-866 exhibited in vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodefficient mice with log cell kills up to 1.2. PX-866 also increased the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts. The results show that PX-866 is a biologically stable broad-spectrum Ptdlns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of Ptdlns-3-kinase signaling in human tumor xenografts. PX-866 exhibits single agent in vivo antitumor activity and increases the antitumor effects of cisplatin and radiation treatment. Copyright © 2004 American Association for Cancer Research.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ihle, NT
Williams, R
Chow, S
Chew, W
Berggren, MI
Paine-Mrrieta, G
Minion, DJ
Halter, RJ
Wipf, Ppwipf@pitt.eduPWIPF
Abraham, R
Kirkpatrick, L
Powis, G
Date: 1 July 2004
Date Type: Publication
Journal or Publication Title: Molecular Cancer Therapeutics
Volume: 3
Number: 7
Page Range: 763 - 772
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 1535-7163
MeSH Headings: Androstadienes--blood; Androstadienes--pharmacology; Androstadienes--toxicity; Androstenes--blood; Androstenes--pharmacology; Androstenes--toxicity; Animals; Antibodies, Phospho-Specific--immunology; Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Bacteriocins--blood; Bacteriocins--pharmacology; Bacteriocins--toxicity; Cell Line, Tumor; Cisplatin--pharmacology; Colonic Neoplasms--enzymology; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; Female; Gonanes--chemistry; Gonanes--pharmacology; Humans; Lung Neoplasms--enzymology; Mice; Mice, SCID; Ovarian Neoplasms--enzymology; Ovarian Neoplasms--radiotherapy; Phosphatidylinositol 3-Kinases--antagonists & inhibitors; Protein-Serine-Threonine Kinases--analysis; Protein-Serine-Threonine Kinases--immunology; Proto-Oncogene Proteins--analysis; Proto-Oncogene Proteins--immunology; Proto-Oncogene Proteins c-akt; Xenograft Model Antitumor Assays
PubMed ID: 15252137
Date Deposited: 30 Jan 2014 18:15
Last Modified: 02 Mar 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/20423

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