Selumetinib (AZD6244)

Catalog No.S1008 Batch:S100834

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Technical Data

Formula

C17H15BrClFN4O3
Molecular Weight 457.68 CAS No. 606143-52-6
Solubility (25°C)* In vitro DMSO 91 mg/mL (198.82 mM)
Water Insoluble
Ethanol Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Selumetinib (AZD6244, ARRY-142886) 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. Selumetinib suppresses cell proliferation, migration and trigger apoptosis. Phase 3.
Targets
MEK1 [1]
(Cell-free assay)		 MEK1 [13]
(Cell-free assay)		 MEK2 [13]
(Cell-free assay)
14 nM 99 nM(Kd) 530 nM(Kd)
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. [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 (from 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

  • Dosages

    50 or 100mg/kg

  • Administration

    Administered via p.o.

Customer Product Validation

Data from [Oncogene, 2012, 31, 3277–3286]

Data from [Nature, 2010, 468, 968-972]

Data from [Nature, 2010, 468, 973-977]

Data from [Clin Cancer Res, 2010, 16, 6029-6039]

Selleck's Selumetinib (AZD6244) has been cited by 776 publications

Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer [ Nature, 2024, 629(8013):927-936] PubMed: 38588697
SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers [ Nat Commun, 2024, 15(1):8002] PubMed: 39266533
SRF SUMOylation modulates smooth muscle phenotypic switch and vascular remodeling [ Nat Commun, 2024, 15(1):6919] PubMed: 39134547
Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer [ Nat Commun, 2024, 15(1):2503] PubMed: 38509064
Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation [ Nat Commun, 2024, 15(1):2843] PubMed: 38565573
EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401 [ Cell Death Differ, 2024, 31(10):1318-1332] PubMed: 38789573
EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401 [ Cell Death Differ, 2024, 10.1038/s41418-024-01316-3] PubMed: 38789573
A split intein and split luciferase-coupled system for detecting protein-protein interactions [ Mol Syst Biol, 2024, 10.1038/s44320-024-00081-2] PubMed: 39668253
ERK1/2 interaction with DHPS regulates eIF5A deoxyhypusination independently of ERK kinase activity [ Cell Rep, 2024, 43(10):114831] PubMed: 39392755
A senescence restriction point acting on chromatin integrates oncogenic signals [ Cell Rep, 2024, 43(4):114044] PubMed: 38568812

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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