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AR-A014418

Name: AR-A014418
Brand: Selleck Chemicals
SKU: S7435
Rating: 5 (17 reviews)

Catalog No.S7435 Synonyms: GSK-3β Inhibitor VIII

For research use only.

AR-A014418 (GSK-3β Inhibitor VIII) is an ATP-competitive, and selective GSK3β inhibitor with IC50 and K_i of 104 nM and 38 nM in cell-free assays, without significant inhibition on 26 other kinases tested.

CAS No. 487021-52-3

Selleck's AR-A014418 has been cited by 17 publications

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GSK-3 Signaling Pathway Map

Biological Activity

Description

Features

Cell-permeable GSK3-selective inhibitor.

Targets

GSK-3β ^[1] (Cell-free assay)	GSK-3β ^[1] (Cell-free assay)
38 nM(Ki)	38 nM(Ki)

In vitro

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. ^[1] While in NGP and SH-5Y-SY cells, AR-A014418 reduces neuroendocrine markers and suppresses neuroblastoma cell growth. ^[2]

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	Formulation	Activity Description	PMID

human BxPC3 cells	MX;Hdo94fGhiaX7obYJqfGmxbjDhd5NigQ>?	Mo\wO\|IhcA>?	MU\Hdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDCfHBEOyClZXzsd{Bi\nSncjC3NkBpenNiYomgUXRUKGG\|c3H5MEBKSzVyPUG0JO69VQ>?	MnnUNVk{Ozh\|NUW=
human HUPT3 cells	MlO0S5Jwf3SqIHnubIljcXSrb36gZZN{[Xl?	M3nMTlczKGh?	M1r1fmdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGhWWFR\|IHPlcIx{KGGodHXyJFczKGi{czDifUBOXFNiYYPzZZktKEmFNUC9NlIh\|ryP	NX7FRZl7OTl\|M{izOVU>
human MIAPaCa2 cells	M2W1eWdzd3e2aDDpcohq[mm2aX;uJIF{e2G7	NXW1dFBtPzJiaB?=	MYDHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDNTWFR[UOjMjDj[YxteyCjZoTldkA4OiCqcoOgZpkhVVSVIHHzd4F6NCCLQ{WwQVI6KM7:TR?=	MlvxNVk{Ozh\|NUW=

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Assay

Methods	Test Index	PMID

Western blot	β-catenin ; β-catenin / GSK3α / GSK3β / Notch1 ; TAK1 / TAB1 / TAB2 / p-p65 / p65	26292722 26147011 23547054
Growth inhibition assay	Cell viability	26292722

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. ^[3] 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. ^[4]

Protocol (from reference)

Kinase Assay: ^[1]	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 Research: ^[1]	Cell lines: N2A cells Concentrations: ~50 μM Incubation Time: 24 h Method: 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.
Animal Research: ^[2]	Animal Models: ALS mouse model with the G93A mutant human SOD1 Dosages: ~4 mg/kg Administration: i.p.

References

[4] Martins DF, et al. J Pain. 2011, 12(3), 315-322.

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Solubility (25°C)

In vitro	DMSO	61 mg/mL (197.85 mM)
	Water	Insoluble
	Ethanol	Insoluble

Chemical Information

Molecular Weight	308.31
Formula	C₁₂H₁₂N₄O₄S
CAS No.	487021-52-3
Storage	3 years	-20°C	powder
Storage	2 years	-80°C	in solvent
Smiles	COC1=CC=C(C=C1)CNC(=O)NC2=NC=C(S2)[N+](=O)[O-]

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