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AR-A014418GSK3β inhibitor, ATP-competitive and selective

AR-A014418

Catalog No. A3184
Size Price Stock Qty
10mM (in 1mL DMSO) $64.00 In stock
Evaluation Sample $28.00 In stock
10mg $68.00 In stock
50mg $189.00 In stock

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Sample solution is provided at 25 µL, 10mM.

Product Citations

1. Lee YC, Chen YJ, et al. "Amsacrine-induced apoptosis of human leukemia U937 cells is mediated by the inhibition of AKT- and ERK-induced stabilization of MCL1. Apoptosis." 2016 Oct 19. PMID:27757735

Quality Control

Chemical structure

AR-A014418

Related Biological Data

AR-A014418

Biological Activity

Description AR-A014418 is an ATP-competitive, and selective inhibitor of GSK3β with IC50 and Ki of 104 nM and 38 nM
Targets GSK-3          
IC50 104 +/- 27 nM          

Protocol

Kinase experiment [1]:

Kinase assays

The competition experiments were carried out in duplicate with 10 concentrations of the inhibitor. The biotinylated peptide substrate was added at 2 μM in an assay buffer containing 6 milliunits of recombinant human GSK3, 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. The reaction was initiated by the addition of 0.04 μCi of [-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. After incubation for 20 min at room temperature, each reaction was 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.

Cell experiment [1]:

Cell lines

3T3 fibroblasts were engineered to stably express four-repeat tau protein

Preparation method

The solubility of this compound in DMSO is >15.4 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

100 nM to 50 μM for 24 h

Applications

AR-A014418 could inhibit the tau phosphorylation at a GSK3-specific site in cells that were stably expressing human four-repeat tau protein. AR-A014418 could also protect N2A neuroblastoma cells against cell death, which was mediated through inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway.

Animal experiment [2]:

Animal models

Male Sprague–Dawley rats

Dosage form

30 μmol/kg, i.p.

Application

The subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, a well-established model for antidepressant efficacy. In addition, the specificity of this effect was supported by the finding that AR-A014418 could decrease both spontaneous and amphetamine-induced activity.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Bhat R, Xue Y, Berg S, Hellberg S, Orm M, Nilsson Y, Radester AC, Jerning E, Markgren PO, Borgegrd T, Nylf M, Giménez-Cassina A, Hernández F, Lucas JJ, Díaz-Nido J, Avila J. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem. 2003;278(46):45937-45.

[2] Gould TD, Einat H, Bhat R, Manji HK. AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol. 2004;7(4):387-90.

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Chemical Properties

Cas No. 487021-52-3 SDF Download SDF
Synonyms AR-AO 14418;AR 0133418;AR 014418;GSK 3β inhibitor
Chemical Name 1-[(4-methoxyphenyl)methyl]-3-(5-nitro-1,3-thiazol-2-yl)urea
Canonical SMILES COC1=CC=C(C=C1)CNC(=O)NC2=NC=C(S2)[N+](=O)[O-]
Formula C12H12N4O4S M.Wt 308.31
Solubility >15.4mg/mL in DMSO Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Research Update

2. Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action. Neuroscience. 2012 Dec 13;226:411-20. doi: 10.1016/j.neuroscience.2012.09.020. Epub 2012 Sep 19.
Abstract
AR-A014418 exhibited evidently anti-hyperalgesic effects in mice with neuropathic pain possibly through reducing proinflammatory cytokines and increasing serotonergic and catecholaminergic pathways, in which intraperitoneal administration of AR-A014418 inhibited PSNL-induced mechanical hyperalgesia and PSNL-induced cold hyperalgesia and prevented the increase of TNF-α and IL-1β without affecting IL-ra and IL-10.
4. The antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3 beta, in mice. J Pain. 2011 Mar;12(3):315-22. doi: 10.1016/j.jpain.2010.06.007. Epub 2010 Aug 12.
Abstract
The treatment of AR-A014418 alone or with formalin inhibited nociception induced by various sources, in which formalin-induced licking was suppressed at the late phase or both phases by AR-A014418 alone of different dosages. The anti-nociceptive effect of AR-A014418 was thought to be induced by glutamatergic system through metabotropic and ionotropic (NMDA) receptors and the inhibition of the cytokine (TNF-α and IL-1β) signaling.

Background

IC50: 104 ± 27 nM

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer’s disease (AD). AR-A014418 is a selective GSK-3 inhibitor.

In vitro: ARA014418 acted as an ATP-competitive manner and did not significantly inhibit cdk2 or cdk5 or 26 other kinases demonstrating high specificity for GSK3. AR-A014418 inhibited tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein [1].

In vivo: ARA014418 induced behavioural changes that were consistent with the effects of antidepressant drugs. Subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, which was a well-established model for antidepressant efficacy. Moreover, the specificity of this effect was supported by our finding that AR-A014418 decreased spontaneous as well as amphetamine-induced activity [2].

Clinical trial: currently no clinical data were available.

References:
[1] Bhat R, Xue Y, Berg S, Hellberg S, Orm M, Nilsson Y, Rades ter AC, Jerning E, Markgren PO, Borgeg rd T, Nyl f M, Giménez-Cassina A, Hernández F, Lucas JJ, Díaz-Nido J, Avila J.  Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem. 2003;278(46):45937-45.
[2] Gould TD, Einat H, Bhat R, Manji HK.  AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Int J Neuropsychopharmacol. 2004;7(4):387-90.