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    AR-A014418 (SN-4521; GSK 3β inhibitor VIII)
    AR-A014418 (SN-4521; GSK 3β inhibitor VIII)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0221
    CAS #: 487021-52-3Purity ≥98%

    Description: AR-A014418 (AR 0133418; SN4521; GSK-3β inhibitor VIII; AR 014418) is a novel, potent, ATP-competitive, and selective inhibitor of GSK3β (Glycogen Synthase Kinase 3β) with the potential for neurodegenerative diseases. It inhibits GSK3β with an IC50 and Ki of 104 nM and 38 nM in cell-free assays, and exhibits little effects on 26 other kinases tested. AR-A014418 also showed potent antiproliferative activity in vitro by suppressing pancreatic cancer cell growth via inhibition of GSK-3-mediated Notch1 expression. 

    References: Cancer Biol Ther. 2014 May;15(5):510-5; Exp Neurol. 2007 Jun;205(2):336-46.

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    Molecular Weight (MW)

    308.31

    Formula

    C12H12N4O4S

    CAS No.

    487021-52-3

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 62 mg/mL (201.09 mM)

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    SMILES

    O=C(NCC1=CC=C(OC)C=C1)NC2=NC=C([N+]([O-])=O)S2

    Synonyms

    GSK-3β Inhibitor VIII;  GSK-3beta Inhibitor VIII; SN 4521; SN-4521; SN4521; AR-A014418; AR-A 014418; AR-A-014418; AR-AO-14418; 

    Chemical Name: N-(4-Methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea

    InChi Key: YAEMHJKFIIIULI-UHFFFAOYSA-N

    InChi Code: InChI=1S/C12H12N4O4S/c1-20-9-4-2-8(3-5-9)6-13-11(17)15-12-14-7-10(21-12)16(18)19/h2-5,7H,6H2,1H3,(H2,13,14,15,17)

    SMILES Code: COc1ccc(cc1)CNC(=O)Nc2ncc(s2)[N+](=O)[O-]


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    In Vitro

    In vitro activity: AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in 3T3 fibroblasts expressing human four-repeat tau protein with IC50 of 2.7 μM, and protects cultured N2A cells from death induced by blocking PI3K/PKB pathway. In hippocampal slices, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide. While in NGP and SH-5Y-SY cells, AR-A014418 reduces neuroendocrine markers and suppresses neuroblastoma cell growth.

     

    Kinase Assay: GSK3 Scintillation Proximity Assay: The competition experiments are carried out in duplicate with 10 concentrations of the inhibitor in clear-bottomed microtiter plates. The biotinylated peptide substrate, biotin-AAEELDSRAGS(PO3H2)PQL, is added at a final concentration of 2 μM in an assay buffer containing 6 milliunits of recombinant human GSK3 (equal mix of both α and β), 12 mM MOPS, pH 7.0, 0.3 mM EDTA, 0.01% β-mercaptoethanol, 0.004% Brij 35, 0.5% glycerol, and 0.5 μg of bovine serum albumin/25 μl and preincubated for 10-15 min. The reaction is initiated by the addition of 0.04 μCi of [γ-33P]ATP and unlabeled ATP in 50 mM Mg(Ac)2 to a final concentration of 1 μM ATP and assay volume of 25 μl. Blank controls without peptide substrate are used. After incubation for 20 min at room temperature, each reaction is terminated by the addition of 25 μl of stop solution containing 5 mM EDTA, 50 μM ATP, 0.1% Triton X-100, and 0.25 mg of streptavidin-coated SPA beads corresponding to ∼35 pmol of binding capacity. After 6 h the radioactivity is determined in a liquid scintillation counter. Inhibition curves are analyzed by non-linear regression using GraphPad Prism. 

     

    Cell Assay: Cell viability is assessed by calcein/propidium iodide uptake. Calcein AM is taken up and cleaved by esterases present within living cells, yielding yellowish-green fluorescence, whereas PI is only taken up by dead cells, which become orange-red fluorescent. In brief, N2A cells are cultured for 2 days in vitro and then treated with 50 μM LY-294002 in the presence of AR-A014418 or vehicle (DMSO) for 24 h. Subsequently, N2A cells are incubated for 30 min with 2 μM PI and 1 μM calcein-AM. The cultures are then rinsed three times with Hanks' buffered saline solution containing 2 mM CaCl2, and the cells are visualized by fluorescence microscopy using a Zeiss Axiovert 135 microscope. Three fields (selected at random) are analyzed per well (∼300 cells/field) in at least three different experiments. Cell death is expressed as percentage of PI-positive cells from the total number of cells. In every experiment, specific cell death is obtained after subtracting the number of dead cells present in vehicle-treated cultures.

    In Vivo

    In ALS mouse model with the G93A mutant human SOD1, AR-A014418 (0-4 mg/kg, i.p.) delays the onset of symptoms, improves motor activity, slows down disease progression, and postpons the endpoint of the disease. In addition, AR-A014418 produces inhibition effect on acetic acid- and formalin-induced nociception in mice by modulating NMDA and metabotropic receptor signaling as well as TNF-α and IL-1β transmission in the spinal cord.

    Animal model

    ALS mouse model with the G93A mutant human SOD1

    Formulation & Dosage

    Dissolved in saline; 4 mg/kg; i.p. injection

    References

    Cancer Biol Ther. 2014 May;15(5):510-5; Exp Neurol. 2007 Jun;205(2):336-46.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    AR-A014418

    Growth inhibition by GSK-3 inhibitor AR-A014418 in neuroblastoma cells. Cancer Biol Ther. 2014 May;15(5):510-5.

    AR-A014418

    AR-A014418 attenuation of apoptosis inhibitor expression in NGP and SH-5Y-SY cells.

    AR-A014418

    Continuous treatment of AR-A014418 is required for growth suppression of NGP and SH-5Y-SY cells.


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