Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling.
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-oxa-cyclopenta[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 immunodeficient 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 PtdIns-3-kinase inhibitor with good pharmacokinetics that causes prolonged inhibition of PtdIns-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.
Ihle
Nathan T
NT
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724-5024, USA.
Williams
Ryan
R
Chow
Sherry
S
Chew
Wade
W
Berggren
Margareta I
MI
Paine-Murrieta
Gillian
G
Minion
Daniel J
DJ
Halter
Robert J
RJ
Wipf
Peter
P
Abraham
Robert
R
Kirkpatrick
Lynn
L
Powis
Garth
G
D000730:Androstadienes / Q000097:blood / Q000494:pharmacology / Q000633:toxicity; D000736:Androstenes / Q000097:blood / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D045163:Antibodies, Phospho-Specific / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001430:Bacteriocins / Q000097:blood / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006067:Gonanes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000532:radiotherapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
D000730:Androstadienes; D000736:Androstenes; D045163:Antibodies, Phospho-Specific; D000970:Antineoplastic Agents; D001430:Bacteriocins; D004791:Enzyme Inhibitors; D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin; C012097:viridin; D000077191:Wortmannin