SB415286 GSK-3 억제제

SB 415286 inhibits GSK3α in an ATP competitive manner with K_i of 31 nM and shows similar potency against GSK3β. This compound has little or no activity against 24 other protein kinases with IC50 > 10 μ M. It stimulates glycogen synthesis in the Chang human liver cell line with EC50 of 2.9 μM, and induces expression of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells. [1] It protects both central and peripheral nervous system neurones in culture from death induced by reduced PI3-kinase pathway activity in a concentration-dependent manner, which is correlated with inhibition of GSK-3 activity and modulation of GSK-3 substrates tau and β-catenin. [2] In L6 myotubes, this chemical induces a much greater activation of GS (6.8-fold) compared to that elicited by insulin (4.2-fold) or Li (4-fold). [3] This compound (10 μM) inhibits rapamycin-induced down-regulation of cyclin D1, and blocks rapamycin and -induced apoptosis, suggesting a critical role for GSK3β in rapamycin-mediated -sensitization. [4] It prevents coxsackievirus-induced cell death in a dose-dependent manner via stabilization of β-catenin. [5] This chemical exerts a protective effect on hydrogen peroxide-induced cell death in B65 rat neuroblastoma cells and neurons, while lithium does not attenuate the toxic effects of hydrogen peroxide. [7] Its treatment potentiates TRAIL- and CH-11-induced apoptosis in HepG2 cells. [8] Inhibition of GSK-3 by this compound causes multiple myeloma (MM) cell growth arrest and apoptosis through the activation of the intrinsic pathway. [9] It decreases the viability of Neuro-2A cells, and induces the accumulation of cells in the G2/M phase of the cell cycle and subsequent apoptosis. [10]

Administration of SB 415286 (~10 mg/kg twice daily) reduces the extent and degree of the trinitrobenzene sulphonic acid (TNBS)-provoked colonic inflammation in the rat, and reduces the fall in body weight, which is related to downregulation of NF-κB activity, involved in the generation of proinflammatory mediators. [6] Treatment with this compound at 1 mg/kg significantly delays the growth of Neuro-2A cells in vivo in nude mice. [10]