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

Nathan T. Ihle, Ryan Williams, Hsiao-Hui Chow, Wade Chew, Margareta I. Berggren, Gillian Paine-Mrrieta, Daniel J. Minion, Robert J. Halter, Peter Wipf, Robert Abraham, Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

255 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)763-772
Number of pages10
JournalMolecular Cancer Therapeutics
Volume3
Issue number7
StatePublished - Jul 2004

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1-Phosphatidylinositol 4-Kinase
Pharmacology
Heterografts
Phosphatidylinositol 3-Kinases
Cisplatin
Inhibitory Concentration 50
Phosphotransferases
PX-866
Radiation Effects
Phosphatidylinositols
Acetic Acid
Ovarian Neoplasms
Colonic Neoplasms
Half-Life
Lung Neoplasms
Neoplasms
Colon
Esters
Pharmacokinetics
Radiation

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Ihle, N. T., Williams, R., Chow, H-H., Chew, W., Berggren, M. I., Paine-Mrrieta, G., ... 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.

Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. / Ihle, Nathan T.; Williams, Ryan; Chow, Hsiao-Hui; Chew, Wade; Berggren, Margareta I.; Paine-Mrrieta, Gillian; Minion, Daniel J.; Halter, Robert J.; Wipf, Peter; Abraham, Robert; Kirkpatrick, Lynn; Powis, Garth.

In: Molecular Cancer Therapeutics, Vol. 3, No. 7, 07.2004, p. 763-772.

Research output: Contribution to journalArticle

Ihle, NT, Williams, R, Chow, H-H, Chew, W, Berggren, MI, Paine-Mrrieta, G, Minion, DJ, Halter, RJ, Wipf, P, Abraham, R, Kirkpatrick, L & Powis, G 2004, 'Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling', Molecular Cancer Therapeutics, vol. 3, no. 7, pp. 763-772.
Ihle, Nathan T. ; Williams, Ryan ; Chow, Hsiao-Hui ; Chew, Wade ; Berggren, Margareta I. ; Paine-Mrrieta, Gillian ; Minion, Daniel J. ; Halter, Robert J. ; Wipf, Peter ; Abraham, Robert ; Kirkpatrick, Lynn ; Powis, Garth. / Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. In: Molecular Cancer Therapeutics. 2004 ; Vol. 3, No. 7. pp. 763-772.
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