Target nature :
GSK-3 (primary target)
CAS n° :
667463-62-9
Mecanism of action :
Inhibitor of protein kinase (Type I, ATP competitor)
Physico-chemical properties :
Solubility in DMSO : > 23 mg/mL (64.58 mM)
Stockage
Powder -20°C 3 years / 4°C 2 years
In solvent -80°C 6 months / -20°C 1 month
Probe availability :
commercial
Princeps reference :
Meijer L et al. 2003. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chemistry & Biology. 10(12):1255-66.
More bibliography :
Sato N, et al. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004 Jan;10(1):55-63. Epub 2003 Dec 21.
Tseng AS, et al. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol. 2006 Sep;13(9):957-63.
Sklirou, A.D. et al. 6-bromo-indirubin-3ß-oxime (6BIO), a Glycogen synthase kinase-3ß inhibitor, activates cytoprotective cellular modules and suppresses cellular senescence-mediated biomolecular damage in human fibroblasts. Sci Rep 7, 11713 (2017). https://doi.org/10.1038/s41598-017-11662-7
Jorda et al (2018) How selective are pharmacological inhibitors of cell-cycle-regulating cyclin-dependent kinases? J.Med.Chem. 61 9105 PMID: 30234987
Other available information on the probe :
6-bromoindirubin-3'-oxime (BIO) is a member of the class of biindoles that is indirubin substituted at position 6 by a bromo group and in which the keto group at position 3' has undergone condensation with hydroxylamine to form the corresponding oxime. It has a role as an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor and an EC 2.7.11.26 (tau-protein kinase) inhibitor. It is a ketoxime, an organobromine compound, a member of oxindoles and a biindole.
Marine natural products and derivatives, selective inhibitors of GSK-3alpha/beta and of few CDKs (notably CDK5/p25).
Other information on the target :
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3¿ (GSK3A) and GSK-3ß (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, and bipolar disorder.
Selectivity profile :
BIO is a potent, selective, reversible and ATP-competitive inhibitor of GSK-3alpha/ß and CDK1-cyclinB complex with IC50s of 5 nM/320 nM/80 nM for (GSK-3alpha/ß)/CDK1/CDK5, respectively.
IC50s & Target
5 nM (IC50) / GSK-3alpha
5 nM (IC50) / GSK-3Beta
80 nM (IC50) / CDK5/p35
320 nM (IC50) /Cdk1/cyclin B
300 nM (IC50) / cdk2/cyclin A
10 µM (IC50) / Cdk4/cyclin D1
10 µM (IC50) / MAPKK
12 µM (IC50) / protein kinase Calpha
BIO is also a pan-JAK inhibitor, with IC50 values of 0.03, 1.5, 8.0, 0.5 ¿M for TYK2, JAK1, JAK2 and JAK3, respectively.
In vivo data :
BIO (50 mg/kg, p.o.) suppresses melanoma tumor growth in a mouse xenograft model.
BALB/c mice (at 6-8 weeks old) and immunodeficient NOD/SCID/IL2Rgamma null (NSG) mice (female at 6-8 weeks old) are used in the assay. A2058 human melanoma cells at 5×106
cells in serum free medium are inoculated subcutaneously into the dorsal area of NSG mice to create xenograft model. When tumors become palpable, BIO or vehicle
control is administered via oral gavage once daily at 50 mg/kg body weight. Tumor growth is monitored every other day. Tumor volumes are measured every 3 to 4 days. Tumor volumes are calculated using the formula: 0.5 × (larger diameter) × (small diameter)
In vitro data :
BIO is a specific inhibitor of glycogen synthase kinase-3 (GSK-3), with IC50 of 5 nM for GSK-3alpha/ß, shows 16-fold selectivity over CDK5. BIO interacts within the ATP binding pocket of these kinases, reduces ß-catenin phosphorylation on a GSK-3-specific site in cellular models, closely mimicks Wnt signaling in Xenopus embryos. In human and mouse embryonic stem cells, BIO maintains the undifferentiated phenotype and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog. BIO-mediated Wnt activation is functionally reversible, as withdrawal of the compound leads to normal multidifferentiation programs in both human and mouse embryonic stem cells. BIO promotes proliferation in mammalian cardiomyocytes. BIO is also a pan-JAK inhibitor, with IC50 values of 0.03, 1.5, 8.0, 0.5 µM for TYK2, JAK1, JAK2 and JAK3, respectively. BIO selectively inhibits phosphorylation of STAT3 and induces apoptosis of human melanoma cells.
Toxicity :
Classification of the substance or mixture
Not a hazardous substance or mixture according to Regulation (EC) No. 1272/2008.
(A low toxicity is reported when used in a mouse xenograft model of melanoma, from the Book, Melanomas: New Insights for the Healthcare Professional, 2012 Edition).
Chaine SMILES :
O=c2[nH]c1cc(Br)ccc1c2=c4[nH]c3ccccc3c4=NO
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