Selumetinib (AZD6244)

Catalog No.S1008

Selumetinib (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. Phase 3.

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Selumetinib (AZD6244) Chemical Structure

Selumetinib (AZD6244) Chemical Structure
Molecular Weight: 457.68

Validation & Quality Control

Cited by 115 publications:

12 customer reviews :

Quality Control & MSDS

Related Compound Libraries

Selumetinib (AZD6244) is available in the following compound libraries:

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Product Information

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  • Research Area
  • Inhibition Profile
  • Combination Therapy
    Combination Therapy

Product Description

Biological Activity

Description Selumetinib (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. Phase 3.
Targets MEK1 [1]
(Cell-free assay)
IC50 14 nM
In vitro 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. [1] AZD6244 is sensitive to Raf mutations in breast cancer cell lines and Ras mutations in NSCLC cell lines. [2]
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. [1] 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. [3] 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. [4]
Features First MEK inhibitor being tested in Phase II clinical trials.

Protocol(Only for Reference)

Kinase Assay:

[1]

Assay of MEK Kinase Activity 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:

[1]

Cell lines Primary HCC cell lines including 2-1318, 4-1318 and 26-1004 cells
Concentrations ~ 10 μM
Incubation Time 24 or 48 hours
Method

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.

Animal Study:

[1]

Animal Models HCC xenografts in mice homozygous for the SCID (severe combined immunodeficiency) mutation
Formulation In water
Dosages 50 or 100mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Huynh H, et al, Mol Cancer Therapy, 2007, 6 (1), 138-146

[2] Garon EB, et al, Mol Cancer Thera, 2010, 9 (7), 1985-1994.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02839720 Not yet recruiting Appearance Distress|Bothered by Itching Skin|Cafe Au Lait Spot|Cutaneous Neurofibroma|Disfigurement|Dysplasia|Neurofibromatosis Type 1|NF1 Gene Mut  ...more Appearance Distress|Bothered by Itching Skin|Cafe Au Lait Spot|Cutaneous Neurofibroma|Disfigurement|Dysplasia|Neurofibromatosis Type 1|NF1 Gene Mutation|Optic Nerve Glioma National Cancer Institute (NCI) January 2017 --
NCT02685657 Not yet recruiting Triple Negative Breast Cancer Russian Academy of Medical Sciences|Russian Society of Cl  ...more Russian Academy of Medical Sciences|Russian Society of Clinical Oncology September 2016 Phase 2
NCT02768766 Not yet recruiting Uveal Melanoma Richard D. Carvajal|AstraZeneca|Melanoma Research Allianc  ...more Richard D. Carvajal|AstraZeneca|Melanoma Research Alliance|Columbia University May 2016 Phase 1
NCT02503358 Not yet recruiting Stage IIIB Non-Small Cell Lung Cancer|Stage IV Non-Small Cell Lung Cancer OHSU Knight Cancer Institute|National Cancer Institute (NCI) February 2016 Phase 1
NCT02586987 Recruiting Lung Cancer|Melanoma|Head and Neck Carcinoma|Gastroesophageal Cancer|Breast Cancer|Pancreatic Adenocarcinoma|Colorectal Cancer AstraZeneca December 2015 Phase 1

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Chemical Information

Download Selumetinib (AZD6244) SDF
Molecular Weight (MW) 457.68
Formula

C17H15BrClFN4O3

CAS No. 606143-52-6
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms ARRY-142886
Solubility (25°C) * In vitro DMSO 91 mg/mL warming (198.82 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 4% DMSO+30% PEG 300+5% Tween 80+ddH2O 10mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 6-(4-bromo-2-chlorophenylamino)-7-fluoro-N-(2-hydroxyethoxy)-3-methyl-3H-benzo[d]imidazole-5-carboxamide

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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