AS703026 is a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo. AS703026 inhibited growth and survival of MM cells and cytokine-induced osteoclast differentiation more potently (9- to 10-fold) than AZD6244. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs).
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Source | PLoS One (2015). Figure 2. AS-703026 |
| Method | trypan blue staining | |
| Cell Lines | RAW 264.7 cells | |
| Concentrations | 10–250 nM | |
| Incubation Time | 24 h | |
| Results | The activity of AS-703026 was dose-dependent, and was most significant at 250 nM |
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Source | PLoS One (2015). Figure 1. AS-703026 |
| Method | MTT assay | |
| Cell Lines | RAW 264.7 cells | |
| Concentrations | 10–250 nM | |
| Incubation Time | 24 h | |
| Results | Significantly, AS-703026 at 10–250 nM dose-dependently inhibited LPS (100 ng/mL)-induced TNFα production in RAW 264.7 cells. Further, TNFα mRNA expression by the LPS treatment was also inhibited |
| Cell Experiment | |
|---|---|
| Cell lines | MM cell lines |
| Preparation method | Cytotoxicity assays. The inhibitory effects of study compounds on MM cell growth and survival were assessed by both [3H]thymidine incorporation and by measuring 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide (MTT; Sigma-Aldrich, St Louis, MO) dye absorbance following the manufacturer's instruction. Cells (104/well for MM cell line, in triplicates and 2-5×105/well for patient MM cells) were cultured in 96-well plates for 3 days (MM cell lines) or 5-days (patient MM cells). For the [3H]thymidine incorporation assay, cells were pulsed with 0.5 μCi (0.0185 MBq)/well [3H]thymidine (Amersham, Pittsburgh, PA) for 6 h (cell lines), harvested onto glass fiber filters, and counted in a β-scintillation counter. Due to low DNA synthesis of patient MM cells, they were pulsed with 2 μCi/well [3H]thymidine and measured during the last 36 h of culture. |
| Concentrations | 0, 2, 20, 200, 2000, 20000 nM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | H929 cells human plasmacytoma xenograft model |
| Formulation | suspended in 0.5% carboxymethylcellulose (CMC)/0.25%Tween20 at 10 mg/ml |
| Dosages | 15 or 30 mg/kg twice daily |
| Administration | orally |
| Molecular Weight | 431.20 |
| Formula | C15H15FIN3O3 |
| CAS Number | 1236699-92-5 |
| 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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