R547 is a potent and selective ATP-competitive CDK inhibitor.In cell-free assays, R547 effectively inhibited CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1 (Ki = 1–3 nmol/L) and was inactive (Ki > 5,000 nmol/L) against a panel of >120 unrelated kinases. In vitro, R547 effectively inhibited the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s ≤ 0.60 μmol/L.
 |
Source | Oncogene (2012). Figure 6. R547 |
| Method | I.P. | |
| Cell Lines | p27−/− male mice | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 13 day | |
| Results | Strikingly, R547 reduced dysplasia (Figure 6D) and also modestly reduced ectopic mitoses but had no effect on progenitor mitoses that are distant or adjacent to phalloidin-marked apical membranes, respectively |
| Cell Experiment | |
|---|---|
| Cell lines | human tumor cell lines HCT116, H460a, MDA-MB-435, DU145, LOX, and A549 |
| Preparation method | Tetrazolium Dye Proliferation [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] Assay |
| Concentrations | 0~1 μM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | HCT116, H460a, MDA-MB-435, DU145, LOX, and A549 |
| Formulation | Oral R547 was formulated as a suspension in Klucel LF/Tween 80, and i.v. R547 was formulated as a solution in hydroxylpropyl β-cyclodextrin, sodium hydroxide, and water for i.v. injection |
| Dosages | 40 mg/kg daily oral dosing and 40 mg/kg i.v. once weekly |
| Administration | oral or i.v. |
| Molecular Weight | 441.45 |
| Formula | C18H21F2N5O4S |
| CAS Number | 741713-40-6 |
| Solubility (25°C) | DMSO 50 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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