PD0166285 is identified to inhibit Wee1 activity at nanomolar concentrations. The inhibitor abrogates G2/M checkpoint inducing early cell division. This G2 checkpoint abrogation by PD0166285 was demonstrated to kill cancer cells, there at a toxic highest dose of 0.5 muM in some cell lines for exposure periods of no longer than 6 hours. PD0166285 does not inhibit Cdc2/cyclin B but inhibits Chk1 kinase at a much higher concentration (3433 nM).
In vivo, PD0166285 at 0.5 μM concentration can inhibit Cdc2Y15/T14 phosphorylation in all cell lines tested, regardless of their p53 status and pharmacological targeting of WEE1 by PD0166285 sensitizes U251-FM GBM tumors to IR in vivo.
| Cell Experiment | |
|---|---|
| Cell lines | B16 mouse melanoma cells |
| Preparation method | B16 cells (1 × 105 cells in 100 mm-dishes) are maintained in medium overnight. In addition, the cells are treated with (0, 0.5, 1.0, or 2.0 μM) PD0166285 (including DMSO vehicle) for indicated times. The cells are washed twice with phosphate-buffered saline (PBS). Next, the cells are trypsinized, so the cell numbers in each dish are determined by using a computed cell-counter (Sysmex CDA-500) according to manufacturer's recommendation. |
| Concentrations | 0.5, 1, 2 μM |
| Incubation time | 4 h, 24 h |
| Animal Experiment | |
|---|---|
| Animal models | Nude mice with implanted GBM cells |
| Formulation | DMSO |
| Dosages | 0, 20, 100, 200, or 400 µM in 100 µl |
| Administration | s.c. |
| Molecular Weight | 512.43 |
| Formula | C26H27Cl2N5O2 |
| CAS Number | 185039-89-8 |
| Solubility (25°C) | DMSO: ≥ 60 mg/mL |
| 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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