Background
CHIR-98014 is a potent inhibitor of GSK-3α and GSK-3β with IC50 values of 0.65 nM and 0.58 nM, respectively [1]
GSK-3 (Glycogen synthase kinase 3) is a serine/threonine protein kinase and plays a pivotal role in a number of central intracellular signaling pathways, including cellular proliferation, migration, inflammation and immune responses, glucose regulation, and apoptosis. Recently, it has been reported that GSK-3 abnormally expressed in a variety of diseases, including Type II diabetes, Alzheimer's Disease, inflammation, cancer, and bipolar disorder [2, 3].
CHIR-98014 is a potent GSK-3α and GSK-3β inhibitor. When tested with insulin receptor-expressing CHO-IR cells or primary rat hepatocytes, CHIR-98014 stimulated the GS activity ratio as high as two- to three fold compared with basal in a dose dependent manner. Similarly, in isolated type 1 skeletal muscle from insulin-sensitive lean Zucker and from insulin-resistant ZDF rats, administration of CHIR-98014 activated GS activity ratio [1]. In mouse ES-D3 cells, CHIR-98014 treatment (48 and 72 hours later) resulted in a significant activation of the Wnt/beta-catenin pathway via inhibiting GSK-3 [4].
In markedly diabetic and insulin-resistant db/db mice model, oral administration of CHIR-98014 (30mg/kg) significantly reduced fasting hyperglycemia within 4 hours and improved glucose disposal during an ipGTT [1].
参考文献:
[1].? Ring, D.B., et al., Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes, 2003. 52(3): p. 588-95.
[2].? Pan WA, et al. The RNA recognition motif of NIFK is required for rRNA maturation during cell cycle progression. RNA Biol. 2015. 12(3):255-67.
[3].? McCubrey JA, et al. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget. 2014. 5(10):2881-911.
[4].? Naujok O, et al. Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. BMC Res Notes. 2014. 7(1):273-281.
Protocol
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Cell experiment:
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Cell lines
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Insulin receptor– expressing CHO-IR cells and primary rat hepatocytes
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Preparation method
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The solubility of this compound in DMSO is <10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
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Reaction Conditions
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24h; EC50=106 nM (CHO-IR cells); EC50=107 nM (rat hepatocytes).
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Applications
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CHIR 98014 resulted in a stimulation of the GS activity ratio above basal. The concentrations of CHIR 98014 causing half-maximal GS stimulation (EC50) were 106 nM for CHO-IR cells and 107 nM for rat hepatocytes.
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Animal experiment:
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Animal models
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Female db/db mice.
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Dosage form
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30 mg/kg; oral taken
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Applications
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Markedly diabetic and insulin-resistant db/db mice treated with 30 mg/kg CHIR 98014 exhibited a significant reduction in fasting hyperglycemia within 4 h of treatment and showed improved glucose disposal during an IPGTT.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1] Ring D B, Johnson K W, Henriksen E J, et al. Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo[J]. Diabetes, 2003, 52(3): 588-595.
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