Description
CHIR99021 is an aminopyrimidine derivative that is an extremely potent glycogen synthase kinase (GSK) 3 inhibitor, inhibiting both GSK3β (IC?? = 6.7 nM) and GSK3α (IC?? = 10 nM). GSK3 is a serine/threonine kinase that is a key inhibitor of the WNT pathway; therefore CHIR99021 functions as a WNT activator. It shows little activity against a large panel of kinases including CDK2 and other serine/threonine kinases such as MAPK and PKB (Bain et al.).
CHIR99021 promotes self-renewal potential of embryonic stem cells (ESCs) of mice by inhibiting glycogen synthase kinase-3 (GSK-3) activity and potentiates the upregulation of β-catenin and c-Myc functions. CHIR99021 promotes self-renewal of ESCs by modulating transforming growth factor β (TGF-β), Notch and mitogen-activated protein kinases (MAPK) signaling pathways. CHIR99021 is an agonist of wingless/integrated (wnt) signalling, upregulates cyclinA expression and promotes cell proliferation in non-small-cell lung cancer (NSCLC) cell lines.
Description
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that plays a key inhibitory role in both the insulin and Wnt signaling pathways. CHIR99021 is an aminopyrimidine derivative that inhibits GSK3α and GSK3β with IC
50 values of 10 and 6.7 nM, respectively. When tested against twenty different protein kinases, this inhibitor shows greater than 500-
fold selectivity for GSK3. CHIR99021 activates glycogen synthesis in CHO-
IR cells (EC
50 = 0.8 μM) and in isolated type 1 diabetic rat skeletal muscle. A single oral dose (30 mg/kg) of CHIR99021 enhances
in vivo glucose metabolism in a rodent model of type 2 diabetes. CHIR99021 has also been shown to induce the reprogramming of murine and human somatic cells into stem cells.
Uses
A specific GSK-3 inhibitor of GSK-3β and GSK-3α with IC50s of 5 nM and 10 nM, respectively.
Uses
CHIR99021 has been used:
- in cocktail with small molecules to convert human lung fibroblast cells into neurons
- as a culture medium supplement in potassium supplemented simplex optimization medium (KSOM) for the culture of blastocysts
- for chronic inhibition of GSK-3 to investigate its role in corticogenesis
Uses
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that plays a key inhibitory role in both the insulin and Wnt signaling pathways. CHIR99021 is an aminopyrimidine derivative that inhibits GSK3α and GSK3β with IC50 values of 10 and 6.7 nM, respectively. When tested against twenty different protein kinases, this inhibitor shows greater than 500-fold selectivity for GSK3. CHIR99021 activates glycogen synthesis in CHO-IR cells (EC50 = 0.8 μM) and in isolated type 1 diabetic rat skeletal muscle. A single oral dose (30 mg/kg) of CHIR99021 enhances in vivo glucose metabolism in a rodent model of type 2 diabetes. CHIR99021 has also been shown to induce the reprogramming of murine and human somatic cells into stem cells.
Application
CHIR 99021 is an aminopyrimidine derivate that is a selective and potent inhibitor of glycogen synthase kinase 3 (GSK-3). It is used to maintain human and mouse stem cell lines and, in combination with other reagents, to chemically reprogram somatic cells into stem cells.
CHIR99021 has been used:
in cocktail with small molecules to convert human lung fibroblast cells into neurons
as a culture medium supplement in potassium supplemented simplex optimization medium (KSOM)
for the culture of blastocysts
for chronic inhibition of GSK-3 to investigate its role in corticogenesis
Definition
ChEBI: A member of the class of aminopyrimidines that is 2-aminopyrimidine substituted at positions N2, 5 and 6 by (5-cyanopyridin-2-yl)ethyl, 4-methylimidazol-2-yl and 2,4-dichlorophenyl groups respectively.
General Description
CHIR99021 is an aminopyrimidine derivative. CHIR99021 promotes self-renewal potential of embryonic stem cells (ESCs) of mice by inhibiting glycogen synthase kinase-3 (GSK-3) activity and potentiates the upregulation of β-catenin and c-Myc functions. CHIR99021 promotes self-renewal of ESCs by modulating transforming growth factor β (TGF-β), Notch and mitogen-activated protein kinases (MAPK) signaling pathways. CHIR99021 is an agonist of wingless/integrated (wnt) signalling, upregulates cyclinA expression and promotes cell proliferation in non-small-cell lung cancer (NSCLC) cell lines.
Biological Activity
CHIR 99021 is a potent and highly selective inhibitor of glycogen synthase kinase 3 (GSK-3) (IC50 values are 6.7 and 10 nM for GSK-3β and GSK-3α respectively). Acts as Wnt activator. Exhibits >500-fold selectivity for GSK-3 over closely related kinases; also displays >800-fold selectivity against 45 additional enzymes and receptors. In combination with the irreversible inhibitor of LSD1 (Cat. No. 3852), CHIR 99021 enables reprogramming of mouse embryonic fibroblasts, transduced by Oct4 and Klf4 only, into iPSCs. CHIR 99021 enhances mouse and human ESC self-renewal when used in combination with PD 0325901 (Cat. No. 4192). CHIR 99021 allows formation of extended pluripotent stem (EPS) cells in combination with (S)-(+)-Dimethindene maleate (Cat.No. 1425), tetracycline antibiotic (Cat.No. 3268) and human leukemia inhibitory factor.
Biochem/physiol Actions
CHIR99021 is a very potent inhibitor of Glycogen synthase kinase 3 (GSK3, IC50 values for GSK3α and GSK3β = 10 and 6.7 nM, respectively). There is no cross-reactivity against CDKs. CHIR99201 potentiates self-renewal of human and mouse embryonic stem cells, and enhances reprogramming of somatic cells into stem cells.
References
1) Bennett et al. (2002), Regulation of Wnt signaling during adipogenesis; J. Biol. Chem., 277 30998
2) Bennett et al. (2005), Regulation of osteoblastogenesis and bone mass by Wnt10b; Proc. Natl. Acad. Sci. USA, 102 3324
3) Mussmann et al. (2007), Inhibition of GSK3 promotes replication and survival of pancreatic beta cells; J. Biol. Chem., 282 12030
4) Manceur et al. (2011), Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors; Exp. Cell. Res., 317 2086
5) Takaoka et al. (2016), Live imaging of transforming growth factor-β activated kinase 1 activation in Lewis Lung carcinoma 3LL cells implanted into syngeneic mice and treated with polyinosinic:polycytidylic acid; Cancer Sci., 107 644 [Focus Citation]
