In vitro: PTC-028 is an orally bioavailable compound that decreases BMI-1 levels by posttranslational modification. PTC-028 treatment selectively inhibits cancer cells in clonal growth and viability assays, whereas normal cells remain unaffected. Hyperphosphorylation-mediated depletion of cellular BMI-1 by PTC-028 coupled with a concurrent temporal decrease in ATP and a compromised mitochondrial redox balance potentiates caspase-dependent apoptosis.
In vivo: In vivo, orally administered PTC-028, as a single agent, exhibits significant antitumor activity comparable with the standard cisplatin/paclitaxel therapy in an orthotopic mouse model of ovarian cancer. After administration of single oral doses to the CD-1 mice, total plasma AUC0-24h are 10.9 and 26.1 mg/h/mL at doses of 10 and 20 mg/kg, showing dose proportional pharmacokinetics. The Cmax for PTC-028 at 10 and 20 mg/kg is 0.79 and 1.49 mg/mL, respectively. The Cmax is reached at both dose levels 1-hour postdose after which plasma concentrations slowly reduce.
| Cell Experiment | |
|---|---|
| Cell lines | Immortalized ovarian surface epithelium (OSE) or the fallopian tube epithelium(FTE) cells and ovarian cancer cells |
| Preparation method | Cells are treated with PTC-028 at the indicated concentrations for 48 hours and cellular viability is assessed using the MTS assay. |
| Concentrations | 0-500 nmol/L |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | Preclinical model of ovarian cancer (NCr-nu mcie; 6 to 8 weeks old) |
| Formulation | 0.5% HPMC,1% Tween 80 |
| Dosages | 10 mg/kg and 20 mg/kg |
| Administration | oral administration |
| Molecular Weight | 405.32 |
| Formula | C19H12F5N5 |
| CAS Number | 1782970-28-8 |
| Form | Solid |
| Solubility (25°C) | 81 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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