AZD 6244

SKU: orb1300969

Description

Selumetinib is a potent, selective, and non-ATP-competitive MEK1/2 inhibitor (IC50=14 nM for MEK1). It exhibits antitumor activity and is clinically used for neurofibromatosis type 1 (NF1). This small molecule is widely applied in oncology research, including in vitro cell signaling studies and in vivo tumor model experiments.

Research Area

Pharmacology & Drug Discovery

Key Properties

• CAS Number: 606143-52-6
• MW: 457.68
• Purity: >98%
• Formula: C₁₇H₁₅BrClFN₄O₃
• SMILES: CN1C=NC2=C(F)C(NC3=CC=C(Br)C=C3Cl)=C(C=C12)C(=O)NOCCO
• Target: Kinase
• Solubility: Soluble in DMSO (up to 50 mg/ml) or in Ethanol (up to 2 mg/ml)

Bioactivity

• Target IC50:
  MEK:12 nM|ERK1/2 phosphorylation:10.3 nM (Malme-3M cells)|MEK1:14 nM (cell free)
• In Vivo:
  METHODS: To assay antitumor activity in vivo, Selumetinib (50 mg/kg, 0.5% hydroxypropyl methyl cellulose and 0.1% Tween 80) was administered by gavage to athymic nu/nu mice bearing MDA-MB-231-LM2 xenografts five times per week for three weeks. for three weeks. RESULTS: In mice treated with Selumetinib, lung metastases were inhibited and tumor cells reversed from a mesenchymal phenotype to an epithelial phenotype.
• In Vitro:
  METHODS: TNBC cell lines MDA-MB-231, MDA-MB-468, SUM149, SUM190, KPL-4, and MDA-IBC-3 were treated with Selumetinib (0-100 µM) for 72 h, and cell viability was measured by WST-1 assay. RESULTS: In MDA-MB-468, SUM190, KPL-4 and MDA-IBC-3 cells, the IC50 was above 20 µM, and in MDA-MAB-231 and SUM149 cells, the IC50 values were 8.6 µM and 10 µM, respectively. METHODS: Breast cancer cells HCC-1937 and MDA-MB-231 were treated with Selumetinib (1-50 µM) for 24 h, and the cell cycle was detected by Flow cytometry. RESULTS: Selumetinib triggered apoptosis and G1 phase block in a dose-dependent manner.
• Cell Research:
  Primary HCC cells were plated at a density of 2.0 × 10^4 per well in growth medium. After 48 h in growth medium, the cell monolayer was rinsed twice with MEM. Cells were treated with various concentrations of AZD6244 (0, 0.5, 1.0, 2.0, 3.0, and 4.0 μmol/L) for 24 or 48 h. Cell viability was determined by the MTT assay. Cell proliferation was assayed using a bromodeoxyuridine kit as described by the manufacturer. Experiments were repeated at least thrice, and the data were expressed as mean ± SE .
• Animal Research:
  HT-29 human colon carcinoma or BxPC3 human pancreatic tumor fragments were implanted s.c. in the flank of nude mice and allowed to grow to 100 to 150 mg. Mice (n = 10 per group) were randomized to treatment groups to receive vehicle (10 mL/kg and 10% ethanol/10% cremophor EL/80% D5W) or ARRY-142886 (10, 25, 50, or 100 mg/kg, oral, BID) on days 1 to 21. Tumors [(W^2 × L) / L] were measured twice weekly. Tumor growth inhibition was calculated as 1 (tumor sizetreated / tumor sizevehicle) on each measurement day. Four hours after the last dose on day 21, three mice per group were euthanized to evaluate pharmacokinetic/pharmacodynamic responses. Tumors were excised and flash frozen. Homogenates were analyzed for phospho-ERK1/2 and ERK1/2 expression by Western blotting as described above. For the HT-29 study, monitoring of tumor regrowth was continued for the remaining seven mice per group until tumors reached 1,000 mm^3, when mice would be sacrificed. There were two BxPC3 tumor xenograft studies. For the first study, one group of mice was treated with the clinical standard of care, gemcitabine, at 160 mg/kg, i.p., every 3rd day for a total of four doses. This dose was determined to be the maximum tolerated dose for gemcitabine in the BxPC3 model on this dosing schedule. To evaluate whether previously treated tumors would be refractory to a second cycle of treatment, a second BxPC3 xenograft study was carried out. Mice were treated with vehicle or ARRY-142886 at 25 or 50 mg/kg, BID, for 21 days. Treatment was stopped and tumors were allowed to grow for an additional 7 days before treatment resumed for another 21-day cycle .

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

ARRY-142886; Selumetinib

Compound Identifiers

PubChem CID

10127622