WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 510328
CAS#: 252935-94-7 (CHIR98014)
Description: CHIR98014, also known as CT-98014, is a reversible, cell-permeable inhibitor of GSK3α and GSK3β (IC50 = 0.65 and 0.58 nM, respectively). It is inactive against a series of other serine/threonine or tyrosine kinases. Through its effects on GSK3, CHIR98014 stimulates glycogen synthase in cells (EC50 = 106 nM), potentiates insulin-dependent glucose transport in isolated muscle strips, and improves glucose disposal in diabetic animals. CHIR98014 also reduces tau phosphorylation in rat brains and supports Wnt signaling during osteogenesis. Note: CHIR98014 has an isomer- CHIR98024 (CT-98024), both of which structure are very similar. Many vendors confused each other.
MedKoo Cat#: 510328
Name: CHIR98014
CAS#: 252935-94-7 (CHIR98014)
Chemical Formula: C20H17Cl2N9O2
Exact Mass: 485.08823
Molecular Weight: 486.31
Elemental Analysis: C, 49.39; H, 3.52; Cl, 14.58; N, 25.92; O, 6.58
Related CAS #: 556813-39-9 (CHIR98024) 252935-94-7 (CHIR98014) CHIR98014 HCl
Synonym: CHIR98014; CHIR-98014; CHIR 98014; CT 98014; CT98014; CT-98014; CHIR98024 isomer; CHIR 98024 isomer; CHIR-98024 isomer; CT98024 isomer; CT 98024 isomer; CT-98024 isomer;
IUPAC/Chemical Name: N6-[2-[[4-(2,4-Dichlorophenyl)-5-(1H-imidazol-1-yl)-2-pyrimidinyl]amino]ethyl]-3-nitro-2,6-pyridinediamine
InChi Key: MDZCSIDIPDZWKL-UHFFFAOYSA-N
InChi Code: InChI=1S/C20H17Cl2N9O2/c21-12-1-2-13(14(22)9-12)18-16(30-8-7-24-11-30)10-27-20(29-18)26-6-5-25-17-4-3-15(31(32)33)19(23)28-17/h1-4,7-11H,5-6H2,(H3,23,25,28)(H,26,27,29)
SMILES Code: NC1=NC(NCCNC2=NC=C(N3C=CN=C3)C(C4=CC=C(Cl)C=C4Cl)=N2)=CC=C1[N+]([O-])=O
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | 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. |
| In vitro activity: | CHIR98 produced dose-dependent reductions of both p-CTNNB (phosphorylated Catenin Beta 1) and p-RB (phosphorylated retinoblastoma), reducing p-RB in SHH (sonic hedgehog)-treated CGNPs (cerebellar granule neuron progenitors) as effectively as SHH deprivation (Fig. 3B). GSK-3 inhibition through CHIR98 increased CDKN1A protein levels in CGNPs compared with controls (Fig. 3B). The decrease in proliferation was not accompanied by increased apoptosis, as CHIR98 did not induce a significant or dose-related increase in cC3 (cleaved caspase-3) (Fig. 3B). In parallel cellular quantifications, we found that CHIR98 reduced the number cells showing p-RB expression, EdU (5-ethynyl-2’-deoxyuridine) incorporation and p-HH3 (histone H3) expression, and fewer cells were observed in S phase and M phase compared with SHH-treated controls (Fig. 3C,D). Treatment of CGNPs with the GSK-3 inhibitors LY2090314 (LY209), AZD1080 or LiCl did not decrease p-RB or p-HH3 levels or reduce EdU incorporation as effectively as CHIR98 at similar concentrations (Fig. S2). These results show that modulation of SHH-driven proliferation by GSK-3 is seen outside of the context of genetic deletion and can be achieved within the dynamic range of physiological GSK-3 activity. Reference: Development. 2019 Oct 15; 146(20): dev177550. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826032/ |
| In vivo activity: | P12 rats were injected i.v. with 30 mg kg−1 of the compound dissolved in DMSO. Different doses, vehicles and routes of administration were tested and brain exposure studies were performed (see Methods section and Table 1). Dissolving the compound in DMSO and injecting it i.v. led to a maximal concentration in the brain of 7 μm (Table 2). Animals were therefore treated i.v. with 30 mg kg−1 CHIR98014 for 1, 2 and 4 h. As shown in Table 1, accumulation of CHIR98014 in the brain reached a peak after 1 h and remained stable even after 2 and 4 h of injection. Tissue analysed by western blotting using a Ser396 p-tau antibody showed a ≈40% reduction in the phosphorylation of 43 and 49 kDa tau in the cortex (Figures 7a–c). A significant, threefold reduction in the 43 kDa isoform was also observed in the hippocampus (Figures 7d and e), while no significant reduction in 49 kDa was observed at any time point (Figures 7d and f). Furthermore, a dose-dependent decrease in p-tau levels was also observed when CHIR98014 was injected i.v. for 1 h at different doses (1–30 mg kg−1) although a significant reduction was only detectable at doses above 10 mg kg−1 (Figures 8a–c). The potency of CHIR98014 correlated well with its maximal brain concentration (7 μm) and IC50 for this compound (3.7 nm, Table 2). At 2 μm, CHIR98014 led to a >90% reduction in p-tau in a human neuronal cell line (Table 2). Reference: Br J Pharmacol. 2007 Nov; 152(6): 959–979. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078230/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 13.24 | 27.23 | |
| DMSO:PBS (pH 7.2) (1:4) | 0.2 | 0.41 | |
| DMF | 1.0 | 2.06 |
The following data is based on the product molecular weight 486.31 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Ocasio JK, Bates RDP, Rapp CD, Gershon TR. GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma. Development. 2019 Oct 10;146(20):dev177550. doi: 10.1242/dev.177550. PMID: 31540917; PMCID: PMC6826032. 2. Qiu YS, Jiang NN, Zhou Y, Yu KY, Gong HY, Liao GJ. LMO3 promotes gastric cancer cell invasion and proliferation through Akt-mTOR and Akt-GSK3β signaling. Int J Mol Med. 2018 May;41(5):2755-2763. doi: 10.3892/ijmm.2018.3476. Epub 2018 Feb 8. PMID: 29436606; PMCID: PMC5846634. 3. Liu H, Zhu J, Mao Z, Zhang G, Hu X, Chen F. Tuft1 promotes thyroid carcinoma cell invasion and proliferation and suppresses apoptosis through the Akt-mTOR/GSK3β signaling pathway. Am J Transl Res. 2018 Dec 15;10(12):4376-4384. PMID: 30662679; PMCID: PMC6325505. 4. Selenica ML, Jensen HS, Larsen AK, Pedersen ML, Helboe L, Leist M, Lotharius J. Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol. 2007 Nov;152(6):959-79. doi: 10.1038/sj.bjp.0707471. Epub 2007 Oct 1. PMID: 17906685; PMCID: PMC2078230. |
| In vitro protocol: | 1. Ocasio JK, Bates RDP, Rapp CD, Gershon TR. GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma. Development. 2019 Oct 10;146(20):dev177550. doi: 10.1242/dev.177550. PMID: 31540917; PMCID: PMC6826032. 2. Qiu YS, Jiang NN, Zhou Y, Yu KY, Gong HY, Liao GJ. LMO3 promotes gastric cancer cell invasion and proliferation through Akt-mTOR and Akt-GSK3β signaling. Int J Mol Med. 2018 May;41(5):2755-2763. doi: 10.3892/ijmm.2018.3476. Epub 2018 Feb 8. PMID: 29436606; PMCID: PMC5846634. |
| In vivo protocol: | 1. Liu H, Zhu J, Mao Z, Zhang G, Hu X, Chen F. Tuft1 promotes thyroid carcinoma cell invasion and proliferation and suppresses apoptosis through the Akt-mTOR/GSK3β signaling pathway. Am J Transl Res. 2018 Dec 15;10(12):4376-4384. PMID: 30662679; PMCID: PMC6325505. 2. Selenica ML, Jensen HS, Larsen AK, Pedersen ML, Helboe L, Leist M, Lotharius J. Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol. 2007 Nov;152(6):959-79. doi: 10.1038/sj.bjp.0707471. Epub 2007 Oct 1. PMID: 17906685; PMCID: PMC2078230. |
1: Samereh S, Hajarian H, Karamishabankareh H, Soltani L, Foroutanifar S. Effects of different concentrations of Chir98014 as an activator of Wnt/beta- catenin signaling pathway on oocyte in-vitro maturation and subsequent embryonic development in Sanjabi ewes. Reprod Domest Anim. 2021 Apr 18. doi: 10.1111/rda.13938. Epub ahead of print. PMID: 33866629.
2: Liu Y, Xue M, Cao D, Qin L, Wang Y, Miao Z, Wang P, Hu X, Shen J, Xiong B. Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells. Genomics. 2021 Mar 2;113(3):1057-1069. doi: 10.1016/j.ygeno.2021.02.017. Epub ahead of print. PMID: 33667649.
3: Mathuram TL, Venkatesan T, Das J, Natarajan U, Rathinavelu A. The apoptotic effect of GSK-3 inhibitors: BIO and CHIR 98014 on H1975 lung cancer cells through ROS generation and mitochondrial dysfunction. Biotechnol Lett. 2020 Aug;42(8):1351-1368. doi: 10.1007/s10529-020-02861-w. Epub 2020 Mar 31. PMID: 32236757.
4: Chen Y, Wu B, Lin J, Yu D, Du X, Sheng Z, Yu Y, An C, Zhang X, Li Q, Zhu S, Sun H, Zhang X, Zhang S, Zhou J, Bunpetch V, El-Hashash A, Ji J, Ouyang H. High- Resolution Dissection of Chemical Reprogramming from Mouse Embryonic Fibroblasts into Fibrocartilaginous Cells. Stem Cell Reports. 2020 Mar 10;14(3):478-492. doi: 10.1016/j.stemcr.2020.01.013. Epub 2020 Feb 20. PMID: 32084387; PMCID: PMC7066361.
5: Ocasio JK, Bates RDP, Rapp CD, Gershon TR. GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma. Development. 2019 Oct 10;146(20):dev177550. doi: 10.1242/dev.177550. PMID: 31540917; PMCID: PMC6826032.
6: Liu H, Zhu J, Mao Z, Zhang G, Hu X, Chen F. Tuft1 promotes thyroid carcinoma cell invasion and proliferation and suppresses apoptosis through the Akt- mTOR/GSK3β signaling pathway. Am J Transl Res. 2018 Dec 15;10(12):4376-4384. PMID: 30662679; PMCID: PMC6325505.
7: Zajkowicz A, Gdowicz-Kłosok A, Krześniak M, Janus P, Łasut B, Rusin M. The Alzheimer's disease-associated TREM2 gene is regulated by p53 tumor suppressor protein. Neurosci Lett. 2018 Aug 10;681:62-67. doi: 10.1016/j.neulet.2018.05.037. Epub 2018 May 26. PMID: 29842899.
8: Qiu YS, Jiang NN, Zhou Y, Yu KY, Gong HY, Liao GJ. LMO3 promotes gastric cancer cell invasion and proliferation through Akt-mTOR and Akt-GSK3β signaling. Int J Mol Med. 2018 May;41(5):2755-2763. doi: 10.3892/ijmm.2018.3476. Epub 2018 Feb 8. PMID: 29436606; PMCID: PMC5846634.
9: Zajkowski T, Nieznanska H, Nieznanski K. Stabilization of microtubular cytoskeleton protects neurons from toxicity of N-terminal fragment of cytosolic prion protein. Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2228-39. doi: 10.1016/j.bbamcr.2015.07.002. Epub 2015 Jul 3. PMID: 26149502.
10: Lian X, Bao X, Al-Ahmad A, Liu J, Wu Y, Dong W, Dunn KK, Shusta EV, Palecek SP. Efficient differentiation of human pluripotent stem cells to endothelial progenitors via small-molecule activation of WNT signaling. Stem Cell Reports. 2014 Nov 11;3(5):804-16. doi: 10.1016/j.stemcr.2014.09.005. Epub 2014 Oct 9. Erratum in: Stem Cell Reports. 2015 Jan 13;4(1):170. PMID: 25418725; PMCID: PMC4235141.
11: Naujok O, Lentes J, Diekmann U, Davenport C, Lenzen S. Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. BMC Res Notes. 2014 Apr 29;7:273. doi: 10.1186/1756-0500-7-273. PMID: 24779365; PMCID: PMC4008422.
12: Guerrero F, Herencia C, Almadén Y, Martínez-Moreno JM, Montes de Oca A, Rodriguez-Ortiz ME, Diaz-Tocados JM, Canalejo A, Florio M, López I, Richards WG, Rodriguez M, Aguilera-Tejero E, Muñoz-Castañeda JR. TGF-β prevents phosphate- induced osteogenesis through inhibition of BMP and Wnt/β-catenin pathways. PLoS One. 2014 Feb 27;9(2):e89179. doi: 10.1371/journal.pone.0089179. Erratum in: PLoS One. 2014;9(6):e101910. PMID: 24586576; PMCID: PMC3937350.
13: Mao J, Hu X, Xiao Y, Yang C, Ding Y, Hou N, Wang J, Cheng H, Zhang X. Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice. Diabetes. 2013 Nov;62(11):3736-46. doi: 10.2337/db13-0035. Epub 2013 Jul 24. PMID: 23884889; PMCID: PMC3806619.
14: Selenica ML, Jensen HS, Larsen AK, Pedersen ML, Helboe L, Leist M, Lotharius J. Efficacy of small-molecule glycogen synthase kinase-3 inhibitors in the postnatal rat model of tau hyperphosphorylation. Br J Pharmacol. 2007 Nov;152(6):959-79. doi: 10.1038/sj.bjp.0707471. Epub 2007 Oct 1. PMID: 17906685; PMCID: PMC2078230.
15: Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T, Wagman AS, Hammond ME, Harrison SD. Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes. 2003 Mar;52(3):588-95. doi: 10.2337/diabetes.52.3.588. PMID: 12606497.
