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-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.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Gonanes/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Androstadienes/blood , Androstadienes/pharmacology , Androstadienes/toxicity , Androstenes/blood , Androstenes/pharmacology , Androstenes/toxicity , Animals , Antibodies, Phospho-Specific/immunology , Antineoplastic Agents/chemistry , Bacteriocins/blood , Bacteriocins/pharmacology , Bacteriocins/toxicity , Cell Line, Tumor , Cisplatin/pharmacology , Colonic Neoplasms/enzymology , Enzyme Inhibitors/chemistry , Female , Gonanes/chemistry , Humans , Lung Neoplasms/enzymology , Mice , Mice, SCID , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/radiotherapy , Protein Serine-Threonine Kinases/analysis , Protein Serine-Threonine Kinases/immunology , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/immunology , Proto-Oncogene Proteins c-akt , Wortmannin , Xenograft Model Antitumor AssaysABSTRACT
A series of viridin analogs was prepared from wortmannin by nucleophilic ring opening at C(20) and evaluated against the signaling kinases PI-3-kinase and mTOR. Several subnanomolar enzyme inhibitors with orders of magnitude selectivity for PI-3-kinase and strong cytotoxic activity against four cancer cell lines were identified. Among the ten most promising derivatives, six demonstrated lower liver toxicity and greater promise for inhibition of tumor cell growth than the lead structure wortmannin.