ckd732 and fumagillin

Fumagillin, an antimicrobial compound first isolated in 1949 from the fungus Aspergillus fumigatus, four decades later was unexpectedly found to inhibit angiogenesis. Interest in developing angiogenesis inhibitor drugs as possible treatments for cancer led to the synthesis of analogs of fumagillin. Preclinical studies of various analog drugs confirmed that they inhibited angiogenesis, but they also were associated with weight loss as an adverse effect. Because adipose tissue can grow and regress throughout adulthood, is highly vascularized, and has angiogenic properties, interest in investigating anti-angiogenic agents in animal models of obesity found that fumagillin analogs caused dose-dependent reversible weight reduction and adipose tissue loss. Beloranib, a fumagillin analog that is an angiogenesis inhibitor and associated with decreased adiposity in animals, has been studied in phase I clinical trials for cancer. It is currently being investigated for the treatment of obesity and related conditions. Three phase I and three phase II studies found significant degrees of weight loss and acceptable tolerability for beloranib compared to placebo, justifying further clinical development of the drug for obesity.

Topics: Angiogenesis Inducing Agents; Animals; Anti-Obesity Agents; Aspergillus; Cinnamates; Cyclohexanes; Epoxy Compounds; Fatty Acids, Unsaturated; Humans; Mice; Obesity; Sesquiterpenes

Inhibition of angiogenesis is emerging as a promising strategy for the treatment of cancer. In our study reported here, the effects of 4 highly potent methionine aminopeptidase 2 (MetAP2) inhibitors, IDR-803, IDR-804, IDR-805 and CKD-732 (designed by structure-based molecular modeling), on angiogenesis and tumor growth were assessed. Concentrations of these inhibitors as low as 2.5 nM were able to inhibit the growth of human umbilical vein endothelial cells (HUVEC) by as much as 50%, arresting growth in the G1 stage of mitosis. An intracellular accumulation of p21(WAF1/Cip1) protein was also observed. Furthermore, at higher concentrations (25 nM) of these 4 MetAP2 inhibitors, a significant induction of apoptosis was apparent in the same HUVEC cultures. As a result of these findings, the possible anticancer effects of these inhibitors were examined, utilizing the SNU-398 hepatoma cell line. Interestingly, pretreatment with these inhibitors led to an increased number of apoptotic cells of up to 60% or more, compared to untreated controls. Moreover, utilizing an in vivo xenografted murine model, these inhibitors suppressed the growth of engrafted tumor. In conclusion, these 4 inhibitory compounds potently exert an antiangiogenic effect to inhibit the growth of cancers in vivo and could potentially be useful for the treatment of a variety of cancers.

Topics: Aminopeptidases; Angiogenesis Inhibitors; Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cinnamates; Cyclohexanes; Disease Models, Animal; Endothelial Cells; Epoxy Compounds; Fatty Acids, Unsaturated; Humans; Liver Neoplasms; Metalloendopeptidases; Mice; Mice, Nude; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Transplantation, Heterologous; Umbilical Veins

The pharmacokinetics of CKD-732 (6-O-4-[dimethyl-aminoethoxy)cinnamoyl]-fumagillol x hemioxalate) was investigated in male SD rats and beagle dogs after bolus intravenous administration. The parent compound and metabolites obtained from in vitro and in vivo samples were determined by LC/MS. The main metabolite was isolated and identified as an N-oxide form of CKD-732 by NMR and LC/MS/MS. CKD-732 was metabolized into either M11 or others by rapid hydroxylation, demethylation, and hydrolysis. The blood level following the intravenous route declined in first-order kinetics with T(1/2)beta values of 0.72 to approximately 0.78 h for CKD-732 and 0.92 to approximately 1.09 h for M11 in rats at a dose of 7.5 to approximately 30 mg/kg. In dogs, T(1/2)beta values of CKD-732 and M11 were 1.54 and 1.79 h, respectively. Moreover, AUC values increased dose dependently for CKD-732 and M11 in rats and dogs. The CLtot and Vdss did not change significantly with increasing dose, indicating linear pharmacokinetic patterns. The excretion patterns through the urine, bile, and feces were also examined in the animals. The total amount excreted in urine, bile, and feces was 2.13% for CKD-732 and 1.29% for M11 in rats, and 1.58% for CKD-732 and 2.28% for M11 in dogs.

Topics: Absorption; Angiogenesis Inhibitors; Animals; Area Under Curve; Bile; Biotransformation; Chromatography, High Pressure Liquid; Cinnamates; Cyclohexanes; Dogs; Epoxy Compounds; Fatty Acids, Unsaturated; Feces; In Vitro Techniques; Infusions, Intravenous; Male; Mice; Mice, Inbred ICR; Microsomes, Liver; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Species Specificity; Tissue Distribution