M.W. 465.34

C22H18Cl2N8

[252917-06-9]

Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO.  Disposal:  A

CHIR99021 specifically inhibits glycogen synthase kinase-3β (GSK3β, IC50 = 5 nm) and GSK3α (IC50 = 10 nm), inhibits preadipocyte differentiation (IC50 = 0.3 µM), possibly by blocking induction of C/EBPα and PPARγ, and mimics Wnt signaling in 3T3-L1 preadipocytes.  Bennett, C.N., et al.  "Regulation of Wnt signaling during adipogenesis."  J. Biol. Chem. 277:  30998-31004 (2002).

CHIR99021 showed highly selective inhibition of GSK-3α and GSK-3β, with IC50s of 10 nM and 6.7 nM, respectively.  It showed a Ki of 9.8 nM for GSK-3β.  However, it exhibited an IC50 of 8800 nM for CDC2. CHIR99021 activates glycogen synthase in CHO-IR cells with EC50 of 763 nM.  ZDF rats display insulin resistance, glucose intolerance, and mild hyperglycemia.  In these rats, a single oral dose of CHIR 99021 rapidly reduced plasma glucose while plasma insulin remained at or below control levels.  ZDF rats treated with CHIR 99021 showed significantly improved glucose tolerance with no significant differences in plasma insulin levels compared with control animals.  Ring, D.B., et al.  "Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo."  J. Biol. Chem. 277:  30998-31004 (2002)Diabetes 52: 588-595 (2003).

Alsterpaullone, kenpaullone, SB 214763, and SB 415286 not only inhibited GSK-3 potently but also blocked CDKs.  In contrast, CHIR99021 showed 350-fold selectivity toward GSK-3 compared to CDKs.  GSK-3 is an important intermediate in the pathway from the insulin receptor to the Thymine-rich Insulin Response Element (TIRE).  Regulation of gene transcription by insulin totally depends on GSK-3 inhibition.  Finlay, D., et al.  "Glycogen synthase kinase-3 regulates IGFBP-1 gene transcription through the thymine-rich insulin response element."  BMC Mol. Biol. 5:  15 (2004).

CHIR99021 induced osteoblastogenesis, increased mineralization, and inhibited adipogenesis in ST2 cells.  Bennett C.N., et al.  "Regulation of osteoblastogenesis and bone mass by Wnt10b."  Proc. Natl. Acad. Sci. USA 102:  3324-3329 (2005).

GSK-3 is a regulator of pancreatic beta cell replication and survival, and the GSK3 inhibitor CHIR99021 increased the rate of INS-1E beta cell replication.  Mussmann, R., et al.  "Inhibition of GSK3 promotes replication and survival of pancreatic beta cells."  J. Biol. Chem. 282:  12030-12037 (2007).

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This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.

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