| Description: |
AZD8330 (ARRY-424704) is a potent, uncompetitive MEK1/MEK2 inhibitor, with an IC50 of 7 nM. |
| Target: |
MEK1:7 nM (IC50)
MEK2:7 nM (IC50) |
| In Vivo: |
In tumour xenograft models, AZD8330 demonstrates dose-dependent tumour growth inhibition of approximately 90% at tolerated doses (1.0 mg/kg once daily [OD])[1]. |
| In Vitro: |
AZD8330 is a selective allosteric MEK1/ MEK2 inhibitor. Exposing human osteosarcoma cell lines MOS, U2OS, and 143B to a concentration of 0.5 μM of Trametinib, AZD8330 or TAK-733 for 6 hours, leads to loss of ERK phosphorylation indicating effective MEK inhibition.The activity of these three inhibitors is tested using concentration ranges in six osteosarcoma cell lines: MOS, U2OS, KPD, ZK58, 143b and Saos-2. All three inhibitors decrease viability of MOS and U2OS and strongly affect 143b. By contrast, viability of KPD, ZK58 and Saos-2 is not affected by any of the three inhibitors[2]. |
| Cell Assay: |
Human osteosarcoma cell lines MOS, U2OS, 143B, ZK58, KPD and Saos-2 are grown in RPMI1640 medium supplemented with 10% fetal bovine serum and 25 U/mL Penicillin and 25 μg/mL of Penicillin-Streptomycin. All cells are cultured in a humidified incubator at 37°C with 5% CO2. Dose response curves for Trametinib, AZD8330 (10 nM, 100 nM, and 1 μM) and TAK-733 in 6 osteosarcoma cell lines as indicated. Cells are exposed for 72 hours. Cells are processed using the ATPlite 1Step kit, followed by luminescence measurement on a plate reader[2]. |
| References: |
[1]. Cohen RB, et al. A phase I dose-finding, safety and tolerability study of AZD8330 in patients with advanced malignancies. Eur J Cancer. 2013 May;49(7):1521-9.
[2]. Baranski Z, et al. MEK inhibition induces apoptosis in osteosarcoma cells with constitutive ERK1/2 phosphorylation. Genes Cancer. 2015 Nov;6(11-12):503-12. |
