SB216763

[Description]:

SB 216763 is potent, selective and ATP-competitive GSK-3 inhibitor with IC50s of 34.3 nM for both GSK-3α and GSK-3β.

[Related Catalog]:

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> PI3K/Akt/mTOR >> GSK-3

Signaling Pathways >> Stem Cell/Wnt >> GSK-3

Research Areas >> Neurological Disease

[Target]

GSK-3α:34.3 nM (IC50)

GSK-3β:34.3 nM (IC50)

[In Vitro]

SB-216763 (10-20 µM) induces β-catenin mediated-transcription in a dose-dependent manner in HEK293 cells. SB-216763 (10, 15 and 20 µM) can maintain mESCs with a pluripotent-like morphology in long-term culture. SB-216763 (10 µM) can maintain J1 mESCs in a pluripotent state for more than a month[2]. SB-216763 inhibits GSK-3 with IC50 of 34 nM[3]. SB-216763 is equally effective at inhibiting human GSK-3α and GSK-3β[5].

[In Vivo]

SB216763 (20 mg/kg, i.v.) significantly improves the survival of BLM-treated mice. Mice randomized to receive BLM plus SB216763 shows a noteworthy reduction, compared with BLM-treated mice. SB216763 (20 mg/kg, i.v.) reduces the magnitude of BLM-induced alveolitis[1]. SB 216763 (0.2 mg/kg, i.v.) with either 17β-E100 or Geni100 reverses the ceiling effect because these agents significantly reduce infarct size when the rabbits' hearts are submitted to 30-min CAO[4].

[Cell Assay]

MESCs maintained with LIF or 10 µM SB-216763 for more than a month are resuspended at 40,000 cells/mL in LIF-free mESC medium. EBs are prepared by a hanging drop procedure. Briefly, 20 µL drops containing mESCs are pipetted on the inside of a 10-cm Petri dish lid. The lids are placed onto Petri dishes containing 10 mL of HBSS and the EBs are allowed to form and grow for 4 days in the incubator. After 4 days, 15-20 EBs are transferred to a well containing LIF-free mESC medium in a 24-well plate. The medium is exchanged every two days and autonomously beating cell aggregates are observed and counted.

[Animal admin]

Mice are allocated to four groups (n=12/group) as follows: 1) intratracheal saline + vehicle (25% dimethyl sulfoxide, 25% polyethylene glycol, and 50% saline), 2) intratracheal saline + SB216763 (20 mg/kg) dissolved in vehicle, 3) intratracheal BLM (3 U/kg) + vehicle, and 4) intratracheal BLM + SB216763 (20 mg/kg) in vehicle. Another set of experiments to assess cytokine expression by reverse transcription-PCR is conducted in the mice (n=12/group) to receive 1) intratracheal saline + vehicle, 2) intratracheal BLM, and 3) intratracheal BLM + SB216763. To induce pulmonary fibrosis, BLM is intratracheally administered in mice (n=15/group) on day 0. BLM and saline-treated mice are administered with SB216763 dissolved in vehicle or vehicle alone intravenously at day 0 and then intraperitoneally twice a week until day 28. Mice are sacrificed by CO2 inhalation on days 2, 7, and 28. In the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) experiments, the cohorts of mice are as follows: saline-treated (n=6), BLM-treated (n=6), and BLM + SB216763-treated (n=6).

[References]

[1]. Gurrieri, et al. 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.Pharmacol.Exp.Ther.2010

[2]. Kirby LA, et al. Glycogen synthase kinase 3 (GSK3) inhibitor, SB-216763, promotes pluripotency in mouse embryonic stem cells.PLoS One. 2012;7(6):e39329. Epub 2012 Jun 26.

[3]. Wang M, et al. The first synthesis of [(11)C]SB-216763, a new potential PET agent for imaging of glycogen synthase kinase-3 (GSK-3).Bioorg Med Chem Lett. 2011 Jan 1;21(1):245-9. Epub 2010 Nov 11.

[4]. The ceiling effect of pharmacological postconditioning with the phytoestrogen genistein is reversed by the GSK3beta inhibitor SB 216763 [3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through mitochondrial ATP-dependent potassium channel opening.

[5]. Coghlan MP, et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol. 2000 Oct;7(10):793-803.

[6]. Wang W, et al. Inhibition of glycogen synthase kinase 3beta ameliorates triptolide-induced acute cardiac injury by desensitizing mitochondrial permeability transition. Toxicol Appl Pharmacol. 2016 Dec 15;313:195-203.

[Related Small Molecules]

CHIR-99021 (CT99021) | TWS119 | LY2090314 | Tideglusib | BIO | Kenpaullone | AR-A014418 | AZD1080 | CHIR-98014 | AZD2858 | Indirubin-3'-monoxime | SB 415286 | Bikinin | RGB-286638 | TDZD-8

[ Density]:
1.5±0.1 g/cm3

[ Boiling Point ]:
598.1±50.0 °C at 760 mmHg

[ Melting Point ]:
287-288.6ºC(lit.)

[ Molecular Formula ]:
C₁₉H₁₂Cl₂N₂O₂

[ Molecular Weight ]:
371.217

[ Flash Point ]:
315.5±30.1 °C

[ Exact Mass ]:
370.027588

[ PSA ]:
51.10000

[ LogP ]:
4.79

[ Appearance of Characters ]:
orange

[ Vapour Pressure ]:
0.0±1.7 mmHg at 25°C

[ Index of Refraction ]:
1.702

[ Storage condition ]:
−20°C

[ Water Solubility ]:
DMSO: 20 mg/mL, soluble

Click to get detail MSDS

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H315-H319-H335

[ Precautionary Statements ]:
P261-P305 + P351 + P338

[ Personal Protective Equipment ]:
dust mask type N95 (US);Eyeshields;Gloves

[ Hazard Codes ]:
Xi: Irritant;

[ Risk Phrases ]:
R36/37/38

[ Safety Phrases ]:
26-36

[ RIDADR ]:
NONH for all modes of transport

[ WGK Germany ]:
3

[ HS Code ]:
2933990090

[ HS Code ]: 2933990090

[ Summary ]:
2933990090. heterocyclic compounds with nitrogen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Lenticular mitoprotection. Part B: GSK-3β and regulation of mitochondrial permeability transition for lens epithelial cells in atmospheric oxygen.

Mol. Vis. 19 , 2451-67, (2013)

Loss of integrity of either the inner or outer mitochondrial membrane results in the dissipation of the mitochondrial electrochemical gradient that leads to mitochondrial membrane permeability transit...

Involvement of the glycogen synthase kinase-3 signaling pathway in TBI pathology and neurocognitive outcome.

PLoS ONE 6(9) , e24648, (2011)

Traumatic brain injury (TBI) sets in motion cascades of biochemical changes that result in delayed cell death and altered neuronal architecture. Studies have demonstrated that inhibition of glycogen s...

Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death.

J. Neurochem. 77 , 94-102 , (2001)

The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as Akt) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen syn...

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