Selumetinib (AZD6244)
Catalog No.S1008 Synonyms: ARRY-142886
Molecular Weight(MW): 457.68
Selumetinib (AZD6244) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Phase 3.
Purity & Quality Control
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Biological Activity
| Description | Selumetinib (AZD6244) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It 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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| Features | First MEK inhibitor being tested in Phase II clinical trials. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| 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] |
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| Cell Data |
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| 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] |
Protocol
| Kinase Assay: |
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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. |
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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.
- [3] Yeh TC, et al, Clin Cancer Res, 2007, 13 (5), 1576-1583.
- [4] Huynh H, et al, Mol Cancer Ther, 2007, 6 (9), 2468-2476.
- [5] Davies BR, et al. Mol Cancer Ther, 2007, 6(8), 2209-2219.
- [6] Morelli MP, et al. Clin Cancer Res, 2012, 18(4), 1051-1062.
- [7] Yuen JS, et al. Int J Oncol, 2012, 41(2), 712-720.
- [8] Leboeuf R, et al. J Clin Endocrinol Metab, 2008, 93(6), 2194-2201.
- [9] Emery CM,, et al. Proc Natl Acad Sci U S A, 2009, 106(48), 20411-20416.
- [10] Friday BB, et al. Cancer Res, 2008, 68(15), 6145-6153.
- [11] Huynh H, et al. J Hepatol, 2010, 52(1), 79-87.
- [12] Diep CH, et al. Clin Cancer Res, 2011, 17(9), 2744-2756.
- [13] Davis MI, et al. Nat Biotechnol. 2011, 29(11):1046-51.
Solubility (25°C)
| In vitro | DMSO | 91 mg/mL warmed (198.82 mM) |
|---|---|---|
| Water | Insoluble | |
| Ethanol | Insoluble | |
| In vivo | Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 4% DMSO+30% PEG 300+5% Tween 80+ddH2O For best results, use promptly after mixing. |
5mg/mL |
* 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 Information
| Molecular Weight | 457.68 |
|---|---|
| Formula | C17H15BrClFN4O3 |
| CAS No. | 606143-52-6 |
| Storage | powder |
| in solvent | |
| Synonyms | ARRY-142886 |
Bio Calculators
Molarity Calculator
Calculate the mass, volume or concentration required for a solution. The Selleck molarity calculator is based on the following equation:
Mass (mg) = Concentration (mM) × Volume (mL) × Molecular Weight (g/mol)
*When preparing stock solutions, please always use the batch-specific molecular weight of the product found on the via label and MSDS / COA (available on product pages).
Dilution Calculator
Calculate the dilution required to prepare a stock solution. The Selleck dilution calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2 ( Input Output )
* When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and MSDS / COA (available online).
Molecular Weight Calculator
Enter the chemical formula of a compound to calculate its molar mass and elemental composition:
Tip: Chemical formula is case sensitive. C10H16N2O2 c10h16n2o2
Instructions to calculate molar mass (molecular weight) of a chemical compound:
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Definitions of molecular mass, molecular weight, molar mass and molar weight:
Molecular mass (molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
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Molarity Calculator
Clinical Trial Information
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|---|
| NCT03433183 | Recruiting | Drug: Selumetinib|Drug: Sirolimus | Malignant Peripheral Nerve Sheath Tumors|Neurofibromatosis 1 | Sarcoma Alliance for Research through Collaboration|United States Department of Defense|AstraZeneca | October 2 2019 | Phase 2 |
| NCT03833427 | Recruiting | Drug: Selumetinib|Biological: Pembrolizumab | Advanced/Metastatic Solid Tumors | Merck Sharp & Dohme Corp. | March 18 2019 | Phase 1 |
| NCT03745989 | Recruiting | Drug: MK-8353|Drug: Selumetinib | Solid Tumors | Merck Sharp & Dohme Corp. | February 22 2019 | Phase 1 |
| NCT03326388 | Not yet recruiting | Drug: Selumetinib | Neurofibromatosis Type 1|Plexiform Neurofibroma|Optic Nerve Glioma | Great Ormond Street Hospital for Children NHS Foundation Trust|AstraZeneca | February 2019 | Phase 1|Phase 2 |
| NCT03705507 | Recruiting | Drug: Selumetinib|Drug: Dexamethasone | Acute Lymphoblastic Leukemia|Acute Lymphoblastic Leukemia Adult|Acute Lymphoblastic Leukemia Pediatric|Acute Lymphoblastic Leukemia in Relapse|Acute Lymphoblastic Leukemia Recurrent | University of Birmingham|Cancer Research UK|AstraZeneca | April 17 2018 | Phase 1|Phase 2 |
| NCT00553332 | Completed | Drug: selumetinib|Other: laboratory biomarker analysis | Liver and Intrahepatic Biliary Tract Cancer|Recurrent Extrahepatic Bile Duct Cancer|Unresectable Extrahepatic Bile Duct Cancer | National Cancer Institute (NCI) | November 2007 | Phase 2 |
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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Frequently Asked Questions
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Question 1:
How about the solubility of S1008? How to prepare for the solution if I need to do the in vivo experiments?
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Answer:
S1008 AZD6244 in vehicle 5% DMSO+30% PEG 300+ddH2O will be a suspension for oral administration. If you want a clear solution for injection, you can dissolve it in 4% DMSO+30% PEG 300+5% Tween 80+ddH2O.
