SB216763S1075

SB 216763 displays similar potency for GSK-3β with 96% inhibition at 10 μM while exhibiting minimal activity against 24 other protein kinases including PKBα and PDK1 with IC50 of >10 μM. SB 216763 stimulates glycogen synthesis in human liver cells with EC50 of 3.6 μM, and induces dose-dependent transcription of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells with a maximum 2.5-fold induction at 5 μM. ^[1] SB 216763 protects the cerebellar granule neurones from apoptotic cell death induced by LY-294002 or potassium-deprivation in a concentration-dependent manner, with a maximal neuroprotection at 3 μM in contrast with the effect of lithium chloride at which 10 mM is required. SB 216763 at 3 μM also completely prevents death of chicken dorsal root ganglion sensory neurones induced by LY-294002 regardless of NGF. SB 216763 treatment at 5 μM markedly inhibits the GSK-3-dependent phosphorylation of neuronal-specific microtubule-associated protein tau in cerebellar granule neurones or recombinant tau in HEK293 cells, and induces increased levels of cytoplasmic β-catenin in both cells mimicking the effect of Wnt-mediated inhibition of GSK-3. ^[2] In pancreatic cancer cell lines including BXPC-3, MIA-PaCa2, PANC1, ASPC1, and CFPAC, SB 216763 treatment at 25-50 μM reduces cell viability in a dose-dependent manner, and leads to significant increase in apoptosis by 50% at 72 hours due to the specific down regulation of GSK-3β, while has no effect in HMEC or WI38 cell lines. ^[3]