BIO

Catalog No.S7198

BIO is a specific inhibitor of GSK-3 with IC50 of 5 nM for GSK-3α/β in a cell-free assay, shows >16-fold selectivity over CDK5, also a pan-JAK inhibitor.

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BIO Chemical Structure

BIO Chemical Structure
Molecular Weight: 356.17

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Product Information

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Product Description

Biological Activity

Description BIO is a specific inhibitor of GSK-3 with IC50 of 5 nM for GSK-3α/β in a cell-free assay, shows >16-fold selectivity over CDK5, also a pan-JAK inhibitor.
Targets GSK-3 [1]
(Cell-free assay)
TYK2 [4]
(Cell-free assay)
CDK5/p35 [1]
(Cell-free assay)
CDK2/CyclinA [1]
(Cell-free assay)

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IC50 5 nM 30 nM 0.08 μM 0.30 μM
In vitro BIO (6-bromoindirubin-3'-oxime) is a specific inhibitor of glycogen synthase kinase-3 (GSK-3), with IC50 of 5 nM for GSK-3α/β, shows >16-fold selectivity over CDK5. BIO interacts within the ATP binding pocket of these kinases, reduces β-catenin phosphorylation on a GSK-3-specific site in cellular models, closely mimicks Wnt signaling in Xenopus embryos. [1] 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. [2] BIO promotes proliferation in mammalian cardiomyocytes. [3]6BIO 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. BIO selectively inhibits phosphorylation of STAT3 and induces apoptosis of human melanoma cells. [4]
In vivo BIO suppresses melanoma tumor growth in a mouse xenograft model. [4]
Features The first pharmacological agent shown to maintain self-renewal in human and mouse embryonic stem cells.

Protocol(Only for Reference)

Kinase Assay: [1]

Kinase assay Kinase activities are assayed in Buffer A or C at 30°C, at a final ATP concentration of 15 μM. Blank values are subtracted and activities calculated as pmoles of phosphate incorporated during a 10 min incubation. Controls are performed with appropriate dilutions of dimethylsulfoxide. In a few cases phosphorylation of the substrate is assessed by autoradiography after SDS-PAGE. GSK-3α/β is purified from porcine brain by affinity chromatography on immobilized axin. It is assayed, following a 1/100 dilution in 1 mg BSA/ml 10 mM DTT, with 5 μl 40 μM GS-1 peptide, a specific GSK-3 substrate, (YRRAAVPPSPSLSRHSSPHQSpEDEEE), in buffer A, in the presence of 15 μM [γ-32P] ATP (3,000 Ci/mmol; 1 mCi/ml) in a final volume of 30 μl. After 30 min incubation at 30°C, 25 μl aliquots of supernatant are spotted onto 2.5 × 3 cm pieces of Whatman P81 phosphocellulose paper, and 20 seconds later, the filters are washed five times (for at least 5 min each time) in a solution of 10 ml phosphoric acid/liter of water. The wet filters are counted in the presence of 1 ml ACS scintillation fluid.

Cell Assay: [1]

Cell lines COS1, Hepa or SH-SY5Y cells
Concentrations ~10 μM
Incubation Time 12 or 24 h
Method COS1, Hepa (wild-type, CEM/LM AhR deficient and ELB1 ARNT deficient), or SH-SY5Y cells are grown in 6 cm culture dishes in Dulbecco's Modified Medium (DMEM) containing 10% fetal bovine serum. For treatment, IO (5 μM), BIO (5 or 10 μM), MeBIO (5 or 50 μM), LiCl (20 or 40 mM), or mock solution (DMSO, 0.5% final concentration) is added to medium when cell density reaches ∼70% confluence. After 12 (SH-SY5Y) or 24 hours, the cells, while still in plate, are lysed with lysis buffer (1% SDS, 1 mM sodium orthovanadate, 10 mM Tris [pH 7.4]). The lysate is passed several times through a 26G needle, centrifuged at 10,000 × g for 5 min, and adjusted to equal protein concentration. About 8 μg of each sample is loaded for immunoblotting. Enhanced chemiluminescence is used for detection. The following primary antibodies are used: mouse anti-β-catenin CT (Upstate Biotechnolgies, Clone 7D8, recognizes total β-catenin), mouse anti-phospho-β-catenin (Upstate Biotechnologies, Clone 8E7, recognizes dephosphorylated β-catenin), mouse anti-GSK-3 β, mouse anti-GSK-3 phosphoTyr216, rabbit anti-AhR (Aryl hydrocarbon receptor), and rabbit anti-actin.

Animal Study: [4]

Animal Models mouse
Formulation freshly prepared in 30% Solutol (Basf) at a concentration of 10 mg/mL.
Dosages 50 mg/kg
Administration Oral gavage

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Meijer L, et al. Chem Biol, 2003, 10(12), 1255-1266.

[2] Sato N, et al. Nat Med, 2004, 10(1), 55-63.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02802319 Not yet recruiting Alveolar Bone Loss The University of Texas Health Science Center at San Antonio July 2017 --
NCT02753439 Not yet recruiting Impacted Third Molar Tooth The Baruch Padeh Medical Center, Poriya|Geistlich Pharma AG February 2017 --
NCT02155764 Not yet recruiting Tooth Extraction|Atrophy of Edentulous Alveolar Ridge I.M. Sechenov First Moscow State Medical University|Centr  ...more I.M. Sechenov First Moscow State Medical University|Central Scientific Research Institute of Dentistry and Maxillo-facial Surgery, Moscow, Russia|Bionova, Skolkovo Community, Russia November 2016 Phase 2
NCT02747823 Not yet recruiting Healthy Cipla BioTec Pvt. Ltd.|Quintiles, Inc. June 2016 Phase 1
NCT02817165 Not yet recruiting Acute Diarrhea The Hospital for Sick Children|McMaster University June 2016 Phase 3

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Chemical Information

Download BIO SDF
Molecular Weight (MW) 356.17
Formula

C16H10BrN3O2

CAS No. 667463-62-9
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms GSK-3 Inhibitor IX, 6-bromoindirubin-3-oxime
Solubility (25°C) * In vitro DMSO 71 mg/mL (199.34 mM)
Ethanol 21 mg/mL (58.96 mM)
Water <1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 2H-Indol-2-one, 6-bromo-3-[(3E)-1,3-dihydro-3-(hydroxyimino)-2H-indol-2-ylidene]-1,3-dihydro-, (3Z)-

Customer Product Validation(1)


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Rating
Source PLoS One 2014 9(7), e100947. BIO purchased from Selleck
Method Western blotting
Cell Lines HCT116p53KO cells
Concentrations 2 mM
Incubation Time
Results As shown in Figure transient GSK3A protein depletion by use of siRNA restored cell death in response to 5FU. In order to chemically inhibit GSK3A, but not GSK3B, enzymatic activity we first screened a number of commercially available inhibitors; in fact, being the ATP-binding pockets of GSK3A and GSK3B very similar, BIO block the activity of both isoforms.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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