GSK461364 is an ATP-competitive inhibitor of Plk1 and forms a rapidly reversible complex with Plk1. It has a 400-fold greater potency for Plk1 than for Plk2 and Plk3. In vitro, this compound showed antiproliferative activity in >120 cancer cell lines tested. GSK461364 demonstrated tumor growth inhibition in animal models. In these xenograft models, GSK461364 showed antitumor activity ranging from complete tumor growth inhibition to growth delay. Interestingly, the compound caused dose-dependent mitotic arrest in Colo205 xenografts in vivo.
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Source | Int J Oncol (2016). Figure 1. GSK461364 |
| Method | Immunoblotting | |
| Cell Lines | U2OS cells | |
| Concentrations | 0.5, 1, 2 μM | |
| Incubation Time | 24 h | |
| Results | OS cells were treated with GSK461364 and the levels of PLK1 and pCDC25C (a downstream effector of PLK1) were measured through western blotting. Except for U2OS in time-dependent studies, decreased level of PLK1 and pCDC25C were noted in all three GSK461364-treated OS cell lines |
| Cell Experiment | |
|---|---|
| Cell lines | MDA-MB-231, A549, and PC3 cell line |
| Preparation method | Cell lines were obtained from American Type Culture Collection and grown in the recommended media at 37°C, 5% CO2 in a humidified incubator. Cells were plated in triplicate 96-well microtiter plates at 1,000 cells per well in culture media. GSK461364A dissolved in DMSO or negative control (0.1% DMSO) were added the following day, and one plate was harvested with 50 μL of CellTiter-Glo (Promega) for a time 0 (T = 0) measurement. Remaining duplicate cell plates were typically incubated for 72 h. Cells were then lysed with 50 μL CellTiter-Glo, and chemiluminescent signal was read on the Wallac EnVision 2100 plate reader. All data were normalized to signal at time of compound addition (T = 0). Curves were analyzed using the XLfit (IDBS Ltd.) curve-fitting tool for Microsoft Excel to determine the gI50 (concentration of 50% growth inhibition relative to T = 0 and Ymax values), the gI-maximum (concentration giving maximum growth inhibition), and the Ymin (bottom of the four-parameter curve at gI-maximum). |
| Concentrations | 0~10 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | mice bearing Colo205 tumor xenograft model |
| Formulation | 4% DMA/Cremaphore (50:50), pH 5.6 |
| Dosages | every 2 d (q2dx6, q2dx12) or every 4 d (q4dx3) at nominal dose levels of 25, 50, and 100 mg/kg/dose |
| Administration | i.p. |
| Molecular Weight | 543.6 |
| Formula | C27H28F3N5O2S |
| CAS Number | 929095-18-1 |
| Solubility (25°C) | DMSO 10 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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