CHIR-98014

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].

References:
[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.

Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo.[Pubmed:12606497]

Diabetes. 2003 Mar;52(3):588-95.

Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.

Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors.[Pubmed:24779365]

BMC Res Notes. 2014 Apr 29;7:273.

BACKGROUND: Small membrane-permeable molecules are now widely used during maintenance and differentiation of embryonic stem cells of different species. In particular the glycogen synthase kinase 3 (GSK3) is an interesting target, since its chemical inhibition activates the Wnt/beta-catenin pathway. In the present comparative study four GSK3 inhibitors were characterized. METHODS: Cytotoxicity and potential to activate the Wnt/beta-catenin pathway were tested using the commonly used GSK3 inhibitors BIO, SB-216763, CHIR-99021, and CHIR-98014. Wnt/beta-catenin-dependent target genes were measured by quantitative PCR to confirm the Wnt-reporter assay and finally EC50-values were calculated. RESULTS: CHIR-99021 and SB-216763 had the lowest toxicities in mouse embryonic stem cells and CHIR-98014 and BIO the highest toxicities. Only CHIR-99021 and CHIR-98014 lead to a strong induction of the Wnt/beta-catenin pathway, whereas BIO and SB-216763 showed a minor or no increase in activation of the Wnt/beta-catenin pathway over the natural ligand Wnt3a. The data from the Wnt-reporter assay were confirmed by gene expression analysis of the TCF/LEF regulated gene T. CONCLUSIONS: Out of the four tested GSK3 inhibitors, only CHIR-99021 and CHIR-98014 proved to be potent pharmacological activators of the Wnt/beta-catenin signaling pathway. But only in the case of CHIR-99021 high potency was combined with very low toxicity.

Stabilization of microtubular cytoskeleton protects neurons from toxicity of N-terminal fragment of cytosolic prion protein.[Pubmed:26149502]

Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2228-39.

Prion protein (PrP) mislocalized in the cytosol has been presumed to be the toxic entity responsible for the neurodegenerative process in transmissible spongiform encephalopathies (TSE), also called prion diseases. The mechanism underlying the neurotoxicity of cytosolic PrP (cytoPrP) remains, however, unresolved. In this study we analyze toxic effects of the cell-penetrating PrP fragment, PrP1-30--encompassing residues responsible for binding and aggregation of tubulin. We have found that intracellularly localized PrP1-30 disassembles microtubular cytoskeleton of primary neurons, which leads to the loss of neurites and, eventually, necrotic cell death. Accordingly, stabilization of microtubules by taxol reduced deleterious effects of cytosolic PrP1-30. Furthermore, we have demonstrated that decreased phosphorylation level of microtubule-associated proteins (MAPs), which also increases stability of microtubular cytoskeleton, protects neurons from the toxic effects of PrP1-30. CHIR98014 and LiCl--inhibitors of glycogen synthase kinase 3 (GSK-3), a major kinase responsible for phosphorylation of MAPs, inhibited PrP1-30-induced disruption of microtubular cytoskeleton and increased viability of peptide-treated neurons. We have also shown that the N-terminal fragment of cytoPrP may cause the loss of dendritic spines. PrP1-30-induced changes at the level of spines have also been prevented by stabilization of microtubules by taxol as well as LiCl. These observations indicate that the neurotoxicity of cytoPrP is tightly linked to the disruption of microtubular cytoskeleton. Importantly, this study implies that lithium, the commonly used mood stabilizer, may be a promising therapeutic agent in TSE, particularly in case of the disease forms associated with accumulation of cytoPrP.

Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of WNT signaling.[Pubmed:25418725]

Stem Cell Reports. 2014 Nov 11;3(5):804-16.

Human pluripotent stem cell (hPSC)-derived endothelial cells and their progenitors may provide the means for vascularization of tissue-engineered constructs and can serve as models to study vascular development and disease. Here, we report a method to efficiently produce endothelial cells from hPSCs via GSK3 inhibition and culture in defined media to direct hPSC differentiation to CD34(+)CD31(+) endothelial progenitors. Exogenous vascular endothelial growth factor (VEGF) treatment was dispensable, and endothelial progenitor differentiation was beta-catenin dependent. Furthermore, by clonal analysis, we showed that CD34(+)CD31(+)CD117(+)TIE-2(+) endothelial progenitors were multipotent, capable of differentiating into calponin-expressing smooth muscle cells and CD31(+)CD144(+)vWF(+)I-CAM1(+) endothelial cells. These endothelial cells were capable of 20 population doublings, formed tube-like structures, imported acetylated low-density lipoprotein, and maintained a dynamic barrier function. This study provides a rapid and efficient method for production of hPSC-derived endothelial progenitors and endothelial cells and identifies WNT/beta-catenin signaling as a primary regulator for generating vascular cells from hPSCs.

CHIR-98014 is a potent, cell-permeable GSK-3 inhibitor with IC50s of 0.65 and 0.58 nM for GSK-3α and GSK-3β, respectively; it shows less potent activities against cdc2 and erk2.

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