AZD8330 (ARRY-424704) is a novel, selective, highly efficacious, uncompetitive MEK inhibitor with an IC50 of 7 nM.AZD8330 demonstrates sub-nanomolar potency in mechanistic (pERK) and low to sub-nanomolar potency in functional (proliferation) assays in MEK 1/2 inhibitor sensitive cell lines.
 |
Source | Eur J Cancer (2013). Figure 4. AZD8330 |
| Method | Western blot | |
| Cell Lines | osteosarcoma cell lines | |
| Concentrations | 0.5 μM | |
| Incubation Time | 6 h | |
| Results | The resistant cell lines KPD, ZK58 and Saos-2 showed no constitutive ERK activation. Exposing MOS, U2OS and 143b to a concentration of 0.5μM of Trametinib, AZD8330 or TAK-733 for 6 hours, led to loss of ERK phosphorylation indicating effective MEK inhibition |
| Cell Experiment | |
|---|---|
| Cell lines | HT-29, Malme-3M, MIA PaCa-2, BxPC3, BT474, Zr-75-1 and Malme-3 cell lines |
| Preparation method | Cellular viability assays Cells plated in 96-well plates were incubated with multiple concentrations of compound for 3 days. The number of viable cells was determined using the CellTiter 96 Aqueous Nonradioactive Cell Proliferation Assay (Promega, Madison, WI). |
| Concentrations | 0~50μM |
| Incubation time | 3 days |
| Animal Experiment | |
|---|---|
| Animal models | HT-29 and BxPC3 xenograft |
| Formulation | 10 mL/kg and 10% ethanol/10% cremophor EL/80% D5W |
| Dosages | 10, 25, 50, or 100 mg/kg BID |
| Administration | oral |
| Molecular Weight | 461.23 |
| Formula | C16H17FIN3O4 |
| CAS Number | 869357-68-6 |
| Solubility (25°C) | DMSO |
| 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.
[2] Yao Yao, et al. Effect of AZD8330 on proliferation and apoptosis of multiple myeloma cells
[3] Caela R Miller, et al. MEK1/2 inhibitors in the treatment of gynecologic malignancies
[4] Akintunde Akinleye, et al. MEK and the inhibitors: from bench to bedside
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