Description
SB-216763 (280744-09-4) is a potent and selective inhibitor of glycogen synthase kinase-1 (GSK-3) IC50=34.3 nM.1 Acts at the ATP-binding domain. Displays protective effects in lung fibrosis mouse model.2 Displays neuroprotective effects on cultured neurons.3 SB-216763 maintains mouse embryonic stem cells in a pluripotent state.4Cell permeable.
Uses
SB 216763 is a potent and selective cell permeale ATP-competitive inhibitor of GSK3a. It stimulates glycogen synthesis in Chang human liver cells.
Uses
SB-216763 was used to inhibit GSK-3β in human brain microvascular endothelial cell line and colorectal cancer cells.
Definition
ChEBI: 3-(2,4-dichlorophenyl)-4-(1-methyl-3-indolyl)pyrrole-2,5-dione is a member of indoles and a member of maleimides.
Biological Activity
Potent and selective glycogen synthase kinase-3 (GSK-3) inhibitor (K i = 9 nM for GSK-3 α ); competes with ATP. Has minimal activity against 24 other protein kinases (IC 50 > 10 μ M). Stimulates glycogen synthesis, gene transcription and is neuroprotective.
Biochem/physiol Actions
SB-216763 is a small molecule that competes with ATP and potently inhibits the activity α and β isozymes of GSK-3. It acts as neuroprotectant and prevents neuronal cell death induced by PI3-kinase pathway. It also delays preconditioning, reduces infarct size and prevents cardiac ischemia.
Background
The maleimide derivative SB216763 is a potent and selective cell permeable inhibitor of glycogen synthase kinase 3. Research studies using peptide-based protein kinase assays show that SB216763 inhibits GSK-3α in an ATP competitive manner with an IC50 of 34 nM, and is an equally effective GSK3-β inhibitor. Similar assays demonstrate that SB216763 does not inhibit as many as 24 other serine/threonine and tyrosine protein kinases. As a consequence of inhibiting GSK-3, SB216763 stimulates glycogen synthesis in human liver cells via glycogen synthase activation and induces expression of a β-catenin regulated reporter gene in HEK293 cells. Furthermore, SB216763 induces accumulation of β-catenin, a key downstream effector in the Wnt signaling pathway, in many cell types. Additional research indicates that SB216763 can prevent neuronal cell death induced by PI3 kinase pathway inhibition. Glycogen synthase kinase 3 inhibitors such as SB216763 can be important research tools in studying the functional role of GSK-3 in cell signaling pathways.
References
[1] M P COGHLAN. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription.[J]. Chemistry & biology, 2000, 7 10: 793-803. DOI:
10.1016/s1074-5521(00)00025-9[2] CARMELA GURRIERI. 3-(2,4-dichlorophenyl)-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione (SB216763), a glycogen synthase kinase-3 inhibitor, displays therapeutic properties in a mouse model of pulmonary inflammation and fibrosis.[J]. Journal of Pharmacology and Experimental Therapeutics, 2010, 332 3: 785-794. DOI:
10.1124/jpet.109.153049[3] D. CROSS. Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death.[J]. Journal of Neurochemistry, 2001, 77 1: 94-102. DOI:
10.1046/j.1471-4159.2001.t01-1-00251.x[4] LESLIE A KIRBY. Glycogen synthase kinase 3 (GSK3) inhibitor, SB-216763, promotes pluripotency in mouse embryonic stem cells.[J]. PLoS ONE, 2012: e39329. DOI:
10.1371/journal.pone.0039329
