P22077 is a potent and selective ubiquitin-specific protease 7 (USP7) inhibitor. P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. P22077 treatment of U2OS cells during release from G1/S arrest induces with hydroxyurea resulted in a dose-dependent loss of claspin protein and a concomitant decrease in phospho Serine 317 Chk1.
 |
Source | Cell Death Dis (2013). Figure 3. P22077 |
| Method | CCK-8 assay | |
| Cell Lines | NB cell | |
| Concentrations | 5 μM | |
| Incubation Time | 24 h | |
| Results | P22077 also significantly enhanced the cytotoxic effect of VP-16 on SH-SY5Y and IMR-32 cells but not on SK-N-AS cells |
 |
Source | Cell Death Dis (2013). Figure 2. P22077 |
| Method | Western Blot | |
| Cell Lines | NB cells | |
| Concentrations | 1 μM | |
| Incubation Time | 16 and 24 h | |
| Results | These results suggest that all P22077-sensitive cell lines possess intact p53 signaling and HDM2 expression, whereas in the two P22077-insensitive cell lines, SK-N-AS and NB-19 possesses mutant p53 or lacks expression of HDM2, respectively. |
| Cell Experiment | |
|---|---|
| Cell lines | The human NB cell lines |
| Preparation method | Cells with or without luciferase expression were seeded in 48-well or 6-well plates at appropriate concentrations. After incubation for 24 h, cells were treated with 0, 10, or 20 μM of P22077 for 24 h at 37 °C. |
| Concentrations | 0, 10, or 20 μM |
| Incubation time | 24 h |
| Animal Experiment | |
|---|---|
| Animal models | The orthotopic NB mouse model |
| Formulation | DMSO |
| Dosages | 15 mg/kg daily |
| Administration | i.p. |
| Molecular Weight | 315.32 |
| Formula | C12H7F2NO3S2 |
| CAS Number | 1247819-59-5 |
| Solubility (25°C) | DMSO 43 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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