Description
AR-A 014418 (487021-52-3) is a selective glycogen synthase kinase 3 (GSK-3) inhibitor, IC50 = 104 nM. Inhibits β-amyloid-mediated neurodegeneration in hippocampal slices. Anti-inflammatory activity. Cell permeable. Active in rodent models.
Chemical Properties
Pale Yellow Solid
Uses
Glycogen Synthase Kinase 3β (GSK-3β) inhibitor.
General Description
A cell-permeable thiazole-containing urea compound that acts as a potent inhibitor of GSK-3. Shown to inhibit GSK-3β with high potency (IC50 = 104 nM). Inhibition is competitive with respect to ATP (Ki = 38 nM). Specificity has been reported using a panel of 28 different kinases, including Cdk2 and Cdk5 (IC50 >100 μM). Shown to prevent tau phosphorylation at a GSK-3-specific site. Also shown to protect neuronal cells against Aβ-mediated neurodegeneration in vitro and reduce tauopathy in mice in vivo (30 μmol/kg delivered with 40% PEG400 and 40% dimethylacetamide in water). Caution: Do not use delivering vehicles containing dimethylamine for in vivo studies, as it is highly toxic to animals. A 25 mM (5 mg/649 μl) solution of GSK-3β Inhibitor VIII (Cat. No. 361557) in DMSO is also available.
Biological Activity
Cell permeable, specific and potent inhibitor of glycogen synthase kinase-3 (GSK-3) (IC50=104nM). Inhibition is competitive with respect to ATP (Ki=38nM).
Biochem/physiol Actions
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer′s disease. GSK3 inhibitor, AR-A014418, inhibits GSK3 (IC50 = 104 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 μM) or 26 other kinases, demonstrating high specificity for GSK3.
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].
Enzyme inhibitor
This ATP-competitive protein kinase inhibitor (FW = 308.31 g/mol; CAS
487021-52-3; Solubility: 62 mg/mL DMSO; <1 mg/mL H2O) selectively
targets glycogen synthase kinase 3β (GSK3β),with IC50 = 104 nM; Ki = 38
nM. Attesting to its high specificity for GSK3, AR-A014418 does not
significantly inhibit Cdk2 or Cdk5 (IC50 > 100 μM) or 26 other kinases.
AR-A014418 inhibits phosphorylation of the microtubule-associated
protein Tau at Ser-396 (i.e., the GSK3-specific site) in cells stably
expressing human four-repeat Tau. AR-A014418 protects N2A
neuroblastoma cells against cell death mediated by inhibition of the
phosphatidylinositol 3-kinase/protein kinase B survival pathway. AR-
A014418 inhibits neurodegeneration mediated by b-amyloid peptide in
hippocampal slices. Treatment of neuroblastoma cell lines with AR-
A014418 reduced the level of GSK-3α phosphorylation at Tyr-279
compared to GSK-3β phosphorylation at Tyr-216, and attenuated growth
via the maintenance of apoptosis.. AR-A014418-dependent
antinociceptive effects are induced by modulation of the glutamatergic
system through metabotropic and ionotropic (NMDA) receptors and the
inhibition of TNF-α and IL-1β cytokine signaling.
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].
References
1) Bhat et al. (2003), Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418; J. Biol. Chem., 278 45937
2) Ramirez et al. (2010), Inhibition of glycogen synthase kinase 3beta (GSK3β) decreases inflammatory responses in brain endothelial cells; Am. J. Pathol., 176 881
