product name Selumetinib (AZD6244)
Description: Selumetinib, also known as AZD6244, is a potent, highly selective MEK1 inhibitor with IC50 of 14 nM in cell-free assays, also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Selumetinib inhibits mitogen-activated protein kinase kinases 1 and 2, which may prevent the activation of MEK1/2-dependent effector proteins and transcription factors, and so may inhibit cellular proliferation in MEK-overexpressing tumor cells.
References: Mol Cancer Ther. 2007 Jan;6(1):138-46; Clin Cancer Res. 2007 Mar 1;13(5):1576-83.
457.68
Formula
C17H15BrClFN4O3
CAS No.
606143-52-6
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 91 mg/mL (198.8 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
4% DMSO+30% PEG 300+5% Tween 80+ddH2O: 5 mg/mL
Synonyms
ARRY-142886
other peoduct :
| In Vitro |
In vitro activity: AZD6244 is not competitive with ATP and inactivates the ERK1/2 phosphorylation with IC50 concentrations below 40 nM. AZD6244 also inhibits the growth of primary HCC cells through inhibition of ERK1/2 and p90RSK phosphorylation, accompanied with elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. AZD6244 has little effects on the p38, c-Jun-NH2-kinase, phosphatidylinositol 3-kinase, and MEK5/ERK5 pathways. AZD6244 is sensitive to Raf mutations in breast cancer cell lines and Ras mutations in NSCLC cell lines. Kinase Assay: Anti-MEK1 antibody is used to immunoprecipitate MEK1 molecules. MEK kinase activity is measured as the ability of immuno-isolated MEK1 to activate recombinant ERK1 in a coupled assay using MBP as the end point of the assay. Phosphorylated MBP is resolved on a 14% SDS-PAGE gel and vacuum-dried before exposure to X-ray film. Cell Assay: Cells (Primary HCC cell lines including 2-1318, 4-1318 and 26-1004 cells) are seeded at a density of 2.0 × 104. After 48 hours incubation, the cells are rinsed twice with culture media. Cells are treated with various concentrations of AZD6244 for 24 or 48 hours. Cell viability is determined by the 3-(4,5-dimethylthiazol-2y1)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell proliferation is assayed using a bromodeoxyuridine kit. |
|---|---|
| In Vivo | AZD6244 significantly inhibits phosphorylation of ERK1/2 in 2-1318, 5-1318, 26-1004 and 4-1318 xenografts and induces apoptosis in primary 2-1318 cells by activating the caspase pathway. AZD6244 could inhibit the tumor growth in HT-29 xenograft, which is a colorectal tumor model carrying a B-Raf mutation, at a dose of 100 mg/kg and the tumor growth inhibition of AZD6244 is better than it of Gemcitabine. Otherwise AZD6244 could inhibit HCC xenografts tumor growth, which associated with increased apoptosis and down-regulation of cell cycle regulators, including cyclin D1, Cdc-2, CDK2 and 4, cyclin B1, and c-Myc |
| Animal model | HCC xenografts in mice homozygous for the SCID (severe combined immunodeficiency) mutation |
| Formulation & Dosage | Dissolved in water; 50 or 100mg/kg; Oral gavage |
| References | Mol Cancer Ther. 2007 Jan;6(1):138-46; Clin Cancer Res. 2007 Mar 1;13(5):1576-83. |
