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.
