SB 216763 is a potent and selective ATP-competitive inhibitor of the serine/threonine protein kinase glycogen synthase kinase-3 (GSK-3) α and β isozymes. Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase that is inhibited by an assortment of extracellular stimuli including insulin, growth factors, cell specification factors, and cell adhesion. SB 216763 displays similar potency for GSK-3β with 96% inhibition at 10 μM while exhibiting minimal activity against 24 other protein kinases (IC50 >10 μM). SB 216763 stimulates glycogen synthesis in Chang human liver cells with an EC50 value of 3.6 µM and induces expression of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells. 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. 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.
|Cell lines||BXPC-3 cells and MIA-PaCa2 cells|
|Preparation method||BXPC-3 cells were treated with DMSO or the indicated concentration of GSK-3β inhibitors (AR-A014418 and SB216763) over the indicated time course. Relative cell viability was measured using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. B, MIA-PaCa2 cells and the normal human mammary epithelial cell line HMEC, and embryonic lung fibroblast cell line WI38 were treated with DMSO or the indicated GSK-3β inhibitor (25 μmol/L).|
|Concentrations||1, 10, 25, 50µM|
|Incubation time||24, 48 or 72h|
|Animal models||saline induced pulmonary fibrosis model of C57BL/6N mice (12 weeks old)|
|Formulation||25% dimethyl sulfoxide, 25% polyethylene glycol, and 50% saline|
|Administration||intravenously twice a week until day 28|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 20 mg/mL|
|Source||PLoS One (2012). Figure 1. SB 216763|
|Method||dual luciferase reporter activity|
|Cell Lines||HEK293 cells|
|Incubation Time||24 h|
|Results||"As expected, HEK293 cells treated with 1–20 μM SB-216763 exhibited a dose-dependent increase in Super TOPFlash activity"|
Glycogen synthase kinase 3 (GSK3) inhibitor, SB-216763, promotes pluripotency in mouse embryonic stem cells.
Kirby LA, et al. PLoS One. 2012;7(6):e39329. PMID: 22745733.
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.
Coghlan MP, et al. Chem Biol. 2000 Oct;7(10):793-803. PMID: 11033082.
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TDZD-8 is a non-ATP competitive GSK-3β inhibitor with IC50 of 2 μM; minimal inhibitory effect observed on CDK1, casein kinase II, PKA and PKC.
LY2090314 is a potent GSK-3 inhibitor for GSK-3α/β with IC50 of 1.5 nM/0.9 nM; may improve the efficacy of platinum-based chemotherapy regimens. Phase 1/2.
AZD1080 is a selective, orally active, brain permeable GSK3 inhibitor, inhibits human GSK3α and GSK3β with Ki of 6.9 nM and 31 nM, respectively.
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