%0 Journal Article
%@ 1535-7163
%A Ihle, NT
%A Williams, R
%A Chow, S
%A Chew, W
%A Berggren, MI
%A Paine-Mrrieta, G
%A Minion, DJ
%A Halter, RJ
%A Wipf, P
%A Abraham, R
%A Kirkpatrick, L
%A Powis, G
%D 2004
%F pittir:20423
%J Molecular Cancer Therapeutics
%N 7
%P 763 - 772
%T Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling
%U http://d-scholarship-dev.library.pitt.edu/20423/
%V 3
%X 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.