SB216763 is a potent and selective GSK-3 inhibitor with IC50 of 34.3 nM for GSK-3α and equally effective at inhibiting human GSK-3β.

SB 216763 displays similar potency for GSK-3β with 96% inhibitionat 10 μM while exhibiting minimal activity against 24 other protein kinasesincluding PKBα and PDK1 with IC50 of >10 μM. SB 216763 stimulates glycogensynthesis in human liver cells with EC50 of 3.6 μM, and induces dose-dependenttranscription of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cellswith a maximum 2.5-fold induction at 5 μM. ^[1] SB216763 protects the cerebellar granule neurones from apoptotic cell deathinduced by LY-294002 or potassium-deprivation in a concentration-dependentmanner, with a maximal neuroprotection at 3 μM in contrast with the effect oflithium chloride at which 10 mM is required. SB 216763 at 3 μM also completelyprevents death of chicken dorsal root ganglion sensory neurones induced byLY-294002 regardless of NGF. SB 216763 treatment at 5 μM markedly inhibits theGSK-3-dependent phosphorylation of neuronal-specific microtubule-associatedprotein tau in cerebellar granule neurones or recombinant tau in HEK293 cells,and induces increased levels of cytoplasmic β-catenin in both cells mimickingthe effect of Wnt-mediated inhibition of GSK-3. ^[2] Inpancreatic cancer cell lines including BXPC-3, MIA-PaCa2, PANC1, ASPC1, andCFPAC, SB 216763 treatment at 25-50 μM reduces cell viability in adose-dependent manner, and leads to significant increase in apoptosis by 50% at72 hours due to the specific down regulation of GSK-3β, while has no effect inHMEC or WI38 cell lines. ^[3]

 Administration of SB 216763 at 20 mg/kg significantly prevents lung inflammation and the subsequent fibrosis in bleomycin (BLM)-induced pulmonary inflammation and fibrosis model in mice by significantly blocking the production of inflammatory cytokines MCP-1 and TNF-α by macrophages, and significantly improves the survival of BLM-treated mice. SB 216763 treatment causes a significant reduction in BLM-induced alveolitis by inhibiting alveolar epithelial cell damage. [4]

 

References

[1] Coghlan MP, et al. Chem Biol, 2000, 7(10), 793-803.

[2] Cross DA, et al. J Neurochem, 2001, 77(1), 94-102.

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