Selumetinib (AZD6244)

Selumetinib (AZD6244) is a potent, highly selective MEK1 inhibitor with IC50 of 14 nM, 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

Product Citations(79)

Customer Reviews(11)

Quality Control & MSDS

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

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Product Information

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Product Description

Biological Activity

Description Selumetinib (AZD6244) is a potent, highly selective MEK1 inhibitor with IC50 of 14 nM, 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]
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.
Solubility 0.5% methylcellulose/0.2% Tween 80, 30 mg/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.

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

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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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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 DMSO
Synonyms ARRY-142886
Solubility (25°C) * In vitro DMSO 92 mg/mL (201 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose/0.2% Tween 80 30 mg/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

Research Area

Customer Reviews (11)


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Rating
Source Nature 2010 468, 968-972. Selumetinib (AZD6244) purchased from Selleck
Method Immunoblotting
Cell Lines A375 cells
Concentrations 1 μM
Incubation Time
Results Ectopic COT expression in A375 and SKMEL28 cells also conferred decreased sensitivity to the MEK inhibitors CI-1040 and AZD6244, suggesting that COT expression alone was sufficient to induce this phenotype. In the setting of ectopic COT expression, exposure to AZD6244 or CI-1040 in combination with PLX470 (1 μM each) reduced cell growth and pERK expression more effectively than did single-agent PLX4720, even at concentrations of 10 μM.

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Rating
Source Nature 2010 468, 973-977. Selumetinib (AZD6244) purchased from Selleck
Method Survival Assay
Cell Lines isogenic cell
Concentrations 0.01-10 μM
Incubation Time 72 h
Results The growth of M249 R4 and Pt55 R was sensitive to MEK inhibition in the presence of PLX4032

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Rating
Source Cancer Res 2010 70, 4709-4718. Selumetinib (AZD6244) purchased from Selleck
Method Immunohistochemical staining and immunoblotting
Cell Lines HCT116 xenografts
Concentrations 25 mg/kg/bid
Incubation Time 21 d
Results AZD6244 significantly suppresses HCT116 colon cancer xenograft tumor growth in vivo.

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Source Cancer Res 2010 70, 4709-4718. Selumetinib (AZD6244) purchased from Selleck
Method Immunoblotting
Cell Lines MDA-MB-435 cells, HCT116 cells, SW620 cells, HT29 cells, WM793 cells
Concentrations 10 μmol/L
Incubation Time 4 h
Results AZD6244 significantly inhibits ERK activation and increases FOXO3a expression in all these cancer cell lines, in which cell cycle arrest and apoptosis are concurrently enhanced.

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Source Clin Cancer Res 2010 16, 6029-6039. Selumetinib (AZD6244) purchased from Selleck
Method Clonogenic assays
Cell Lines melanoma cell lines
Concentrations 5000 nM
Incubation Time
Results Combinations were more effective in inhibiting colony formation at lower concentrations than either drug alone.

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Source Br J Haematol 2010 149, 537–549. Selumetinib (AZD6244) purchased from Selleck
Method [3H]thymidine uptake assay/TRAP assay
Cell Lines INA-6 MM cells, PBMCs
Concentrations 2-20000 nmol/l
Incubation Time 2/14 d
Results AS703026 inhibited growth of MM cells more potently than AZD6244 (Figs B). For example, the IC50 of AS703026 and AZD6244 against INA-6 cells was 10 and 100 nmol/l, respectively. AS703026 was also approximately 10-fold more potent than AZD6244 at inhibiting cytokine-induced osteoclast differentiation in vitro, as measured by number of TRAP-positive multinuclear cells following treatment of PBMCs with RANKL and M-CSF(Fig D).

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Source PNAS 2009 106, 20411-20416. Selumetinib (AZD6244) purchased from Selleck
Method Cell growth inhibition assays
Cell Lines melanoma cells
Concentrations 0.001-100 μM
Incubation Time 16 h
Results The GI50 for AZD6244 was 10-50 nM in treatment-naïve BRAFV600E melanoma cultures (WM3482, WM3457, and WM3506) but exceeded 2 μM in cells derived from the AZD6244-resistant metastasis (M307; Fig. A ). Likewise, marked biochemical inhibition of p-ERK was achieved follow ing a 16-hour exposure to 400 nM AZD6244 in treatment-naïve lines, but p-ERK remained robust in the resist ant cells even at 10 MAZD6244 (Fig. B ). Next, we introduced recombinant MEK1(P124L) into parental A375 cells and examined pharmacological resistance to MEK inhibition. As observed with the MEK1(P124S) allele above, MEK1(P124L) ex pression resulted in an ≈5-fold increase in AZD6244 GI50 when c ompared to A375, MEK-WT, or MEK-DD (Fig. C). Similarly, MEK1(P124L) conferred sustained p-ERK expression following exposure to varying concentrations of MEK inhibitor, with measureable p-ERK even at 2 μM of AZD6244 (Fig. D ). In contrast, parental A375 cells and those expressing

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Rating
Source Dr. Jong-In Park of Medical College of Wisconsin. Selumetinib (AZD6244) purchased from Selleck
Method Western Blot
Cell Lines A375 cells
Concentrations 0-10 μM
Incubation Time 1/24 h
Results

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Source Oncogene, 2012, 31, 3277–3286. Selumetinib (AZD6244) purchased from Selleck
Method Western Blot
Cell Lines HEK-293 cells
Concentrations 1 uM
Incubation Time
Results We cultured HEK-293 cellsstably overexpressing p37d or p110d with the general PI3K –inhibitor, LY294002, or the MAPK-inhibitor, AZD6244. The inhibitors strongly affected the levels ofphosphorylated AKT S473 and ERK.

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Rating
Source Nat Genet, 2011, 43(11), 1119-26.. Selumetinib (AZD6244) purchased from Selleck
Method Immunoblot analysis/Flow cytometry analysis
Cell Lines melanoma cell lines
Concentrations 0-30 μM
Incubation Time 1 h/72 h
Results Exposure of melanoma cells to AZD-6244 inhibited MEK in mutant as well as in wild-type cells (Fig. a). exposure of most melanoma cells expressing mutant forms of GRM3 were 2–200-fold more sensitive to AZD-6244 compared to wild-type GRM3 cells (Fig. b). melanoma cell lines harboring mutant GRM3 are markedly more sensitive to MEK1/2 inhibition by AZD-6244, leading to increased cell death.

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Rating
Source Selumetinib (AZD6244) purchased from Selleck
Method Western Blot
Cell Lines HeLa cells
Concentrations 0/10/100/1000 nM
Incubation Time 24 h
Results

Product Citations (79)

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