GSK-J4 free base
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MedKoo CAT#: 555282

CAS#: 1373423-53-0 (free base)

Description: GSK-J4 is a cell permeable, potent and selective histone demethylase. GSK-J4 is a prodrug of GSK J1, which is the first selective inhibitor of the H3K27 histone demethylase JMJD3 and UTX with IC50 of 60 nM in a cell-free assay and inactive against a panel of demethylases of the JMJ family. GSK-J4 is used to probe the consequences of demethylation of H3K27me3. GSK-J4 inhibits the lipopolysaccharide-induced production of cytokines, including pro-inflammatory tumour necrosis factor (TNF).

Chemical Structure

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GSK-J4 free base
CAS# 1373423-53-0 (free base)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 555282
Name: GSK-J4 free base
CAS#: 1373423-53-0 (free base)
Chemical Formula: C24H27N5O2
Exact Mass: 417.22
Molecular Weight: 417.513
Elemental Analysis: C, 69.04; H, 6.52; N, 16.77; O, 7.66

Price and Availability

Size Price Availability Quantity
100mg USD 850 2 weeks
200mg USD 1450 2 weeks
500mg USD 2450 2 weeks
1g USD 3450 2 weeks
2g USD 5450 2 weeks
5g USD 8450 2 weeks
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Related CAS #: 1797983-09-5 (HCl)   1373423-53-0 (free base)    

Synonym: GSK-J4 free base; GSK-J-4; GSK-J 4; GSK-J4;

IUPAC/Chemical Name: ethyl 3-((2-(pyridin-2-yl)-6-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)pyrimidin-4-yl)amino)propanoate

InChi Key: WBKCKEHGXNWYMO-UHFFFAOYSA-N

InChi Code: InChI=1S/C24H27N5O2/c1-2-31-23(30)10-14-26-21-17-22(28-24(27-21)20-9-5-6-13-25-20)29-15-11-18-7-3-4-8-19(18)12-16-29/h3-9,13,17H,2,10-12,14-16H2,1H3,(H,26,27,28)

SMILES Code: O=C(OCC)CCNC1=NC(C2=NC=CC=C2)=NC(N3CCC4=CC=CC=C4CC3)=C1

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

Shelf Life: >3 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: 2934.99.03.00

More Info:

Product Data:
Product Data
Instruction:
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Biological target: GSK-J4 is a potent dual inhibitor of H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A with IC50s of 8.6 and 6.6 μM, respectively. GSK-J4 inhibits LPS-induced TNF-α production in human primary macrophages with an IC50 of 9 μM.
In vitro activity: Hence, this study analyzed the LDH level in the culture medium of AC16 cell (Figure 1F) and neonatal rat cardiomyocyte (NRCM) (Figure 1G) and found that PA (palmitic acid) could stimulate LDH release, while GSK-J4 significantly reduced its releasement. Reference: Front Cardiovasc Med. 2022 Jun 2;9:907747. https://pubmed.ncbi.nlm.nih.gov/35722096/
In vivo activity: There was a significant increase in the amount of α-SMA, fibronectin, and fibronectin as well as collagen IV protein accumulations (Figure 4), whereas in STZ (streptozotocin)-induced diabetic mice that were treated with GSK-J4, the staining areas of fibronectin and collagen IV fibrosis-related proteins were reduced relative to those that were not treated with GSK-J4 (Figure 3). In addition, the accumulation of α-SMA, fibronectin, and collagen IV proteins in the kidneys of the diabetic mice that were given GSK-J4 was also significantly lower than in those that were not given GSK-J4 (Figure 4). Reference: Int J Mol Sci. 2022 Aug 20;23(16):9407. https://pubmed.ncbi.nlm.nih.gov/36012674/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 38.9 93.11
Ethanol 41.8 100.00

Preparing Stock Solutions

The following data is based on the product molecular weight 417.51 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.

Recalculate based on batch purity %
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. Xu K, Liu X, Wen B, Liu Y, Zhang W, Hu X, Chen L, Hang W, Chen J. GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis. Front Cardiovasc Med. 2022 Jun 2;9:907747. doi: 10.3389/fcvm.2022.907747. PMID: 35722096; PMCID: PMC9200982. 2. Illiano M, Conte M, Salzillo A, Ragone A, Spina A, Nebbioso A, Altucci L, Sapio L, Naviglio S. The KDM Inhibitor GSKJ4 Triggers CREB Downregulation via a Protein Kinase A and Proteasome-Dependent Mechanism in Human Acute Myeloid Leukemia Cells. Front Oncol. 2020 Jun 5;10:799. doi: 10.3389/fonc.2020.00799. PMID: 32582541; PMCID: PMC7289982. 3. Hung PH, Hsu YC, Chen TH, Ho C, Lin CL. The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation. Int J Mol Sci. 2022 Aug 20;23(16):9407. doi: 10.3390/ijms23169407. PMID: 36012674; PMCID: PMC9409090. 4. Sanchez A, Penault-Llorca F, Bignon YJ, Guy L, Bernard-Gallon D. Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts. Cancer Genomics Proteomics. 2022 May-Jun;19(3):339-349. doi: 10.21873/cgp.20324. PMID: 35430567; PMCID: PMC9016480.
In vitro protocol: 1. Xu K, Liu X, Wen B, Liu Y, Zhang W, Hu X, Chen L, Hang W, Chen J. GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis. Front Cardiovasc Med. 2022 Jun 2;9:907747. doi: 10.3389/fcvm.2022.907747. PMID: 35722096; PMCID: PMC9200982. 2. Illiano M, Conte M, Salzillo A, Ragone A, Spina A, Nebbioso A, Altucci L, Sapio L, Naviglio S. The KDM Inhibitor GSKJ4 Triggers CREB Downregulation via a Protein Kinase A and Proteasome-Dependent Mechanism in Human Acute Myeloid Leukemia Cells. Front Oncol. 2020 Jun 5;10:799. doi: 10.3389/fonc.2020.00799. PMID: 32582541; PMCID: PMC7289982.
In vivo protocol: 1. Hung PH, Hsu YC, Chen TH, Ho C, Lin CL. The Histone Demethylase Inhibitor GSK-J4 Is a Therapeutic Target for the Kidney Fibrosis of Diabetic Kidney Disease via DKK1 Modulation. Int J Mol Sci. 2022 Aug 20;23(16):9407. doi: 10.3390/ijms23169407. PMID: 36012674; PMCID: PMC9409090. 2. Sanchez A, Penault-Llorca F, Bignon YJ, Guy L, Bernard-Gallon D. Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts. Cancer Genomics Proteomics. 2022 May-Jun;19(3):339-349. doi: 10.21873/cgp.20324. PMID: 35430567; PMCID: PMC9016480.

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1: Wu W, Qin M, Jia W, Huang Z, Li Z, Yang D, Huang M, Xiao C, Long F, Mao J, Moore PK, Liu X, Zhu YZ. Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis. Cell Mol Immunol. 2018 May 29. doi: 10.1038/s41423-018-0037-8. [Epub ahead of print] PubMed PMID: 29844591.

2: Daures M, Idrissou M, Judes G, Rifaï K, Penault-Llorca F, Bignon YJ, Guy L, Bernard-Gallon D. A new metabolic gene signature in prostate cancer regulated by JMJD3 and EZH2. Oncotarget. 2018 May 4;9(34):23413-23425. doi: 10.18632/oncotarget.25182. eCollection 2018 May 4. PubMed PMID: 29805743; PubMed Central PMCID: PMC5955128.

3: Lochmann TL, Powell KM, Ham J, Floros KV, Heisey DAR, Kurupi RIJ, Calbert ML, Ghotra MS, Greninger P, Dozmorov M, Gowda M, Souers AJ, Reynolds CP, Benes CH, Faber AC. Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma. Sci Transl Med. 2018 May 16;10(441). pii: eaao4680. doi: 10.1126/scitranslmed.aao4680. PubMed PMID: 29769286.

4: Guo Z, Lu J, Li J, Wang P, Li Z, Zhong Y, Guo K, Wang J, Ye J, Liu P. JMJD3 inhibition protects against isoproterenol-induced cardiac hypertrophy by suppressing β-MHC expression. Mol Cell Endocrinol. 2018 May 10. pii: S0303-7207(18)30157-6. doi: 10.1016/j.mce.2018.05.009. [Epub ahead of print] PubMed PMID: 29753027.

5: Chen Y, Liu Z, Pan T, Chen E, Mao E, Chen Y, Tan R, Wang X, Tian R, Liu J, Qu H. JMJD3 is involved in neutrophil membrane proteinase 3 overexpression during the hyperinflammatory response in early sepsis. Int Immunopharmacol. 2018 Jun;59:40-46. doi: 10.1016/j.intimp.2018.03.027. Epub 2018 Apr 3. PubMed PMID: 29621735.

6: Li Y, Zhang M, Sheng M, Zhang P, Chen Z, Xing W, Bai J, Cheng T, Yang FC, Zhou Y. Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia. J Cancer Res Clin Oncol. 2018 Jun;144(6):1065-1077. doi: 10.1007/s00432-018-2631-7. Epub 2018 Mar 28. PubMed PMID: 29594337; PubMed Central PMCID: PMC5948279.

7: Jia W, Wu W, Yang D, Xiao C, Su Z, Huang Z, Li Z, Qin M, Huang M, Liu S, Long F, Mao J, Liu X, Zhu YZ. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis. FASEB J. 2018 Jul;32(7):4031-4042. doi: 10.1096/fj.201701483R. Epub 2018 Feb 26. PubMed PMID: 29481307.

8: Park JW, Cho H, Oh H, Kim JY, Seo SB. AURKA Suppresses Leukemic THP-1 Cell Differentiation through Inhibition of the KDM6B Pathway. Mol Cells. 2018 May 31;41(5):444-453. doi: 10.14348/molcells.2018.2311. Epub 2018 Feb 23. PubMed PMID: 29477140; PubMed Central PMCID: PMC5974621.

9: Cribbs A, Hookway ES, Wells G, Lindow M, Obad S, Oerum H, Prinjha RK, Athanasou N, Sowman A, Philpott M, Penn H, Soderstrom K, Feldmann M, Oppermann U. Inhibition of histone H3K27 demethylases selectively modulates inflammatory phenotypes of natural killer cells. J Biol Chem. 2018 Feb 16;293(7):2422-2437. doi: 10.1074/jbc.RA117.000698. Epub 2018 Jan 4. PubMed PMID: 29301935; PubMed Central PMCID: PMC5818173.

10: Rejlova K, Musilova A, Kramarzova KS, Zaliova M, Fiser K, Alberich-Jorda M, Trka J, Starkova J. Low HOX gene expression in PML-RARα-positive leukemia results from suppressed histone demethylation. Epigenetics. 2018;13(1):73-84. doi: 10.1080/15592294.2017.1413517. Epub 2018 Feb 7. PubMed PMID: 29224413; PubMed Central PMCID: PMC5836981.

11: Mandal C, Kim SH, Kang SC, Chai JC, Lee YS, Jung KH, Chai YG. GSK-J4-Mediated Transcriptomic Alterations in Differentiating Embryoid Bodies. Mol Cells. 2017 Oct;40(10):737-751. doi: 10.14348/molcells.2017.0069. Epub 2017 Oct 17. PubMed PMID: 29047260; PubMed Central PMCID: PMC5682251.

12: Taube JH, Sphyris N, Johnson KS, Reisenauer KN, Nesbit TA, Joseph R, Vijay GV, Sarkar TR, Bhangre NA, Song JJ, Chang JT, Lee MG, Soundararajan R, Mani SA. The H3K27me3-demethylase KDM6A is suppressed in breast cancer stem-like cells, and enables the resolution of bivalency during the mesenchymal-epithelial transition. Oncotarget. 2017 Jul 10;8(39):65548-65565. doi: 10.18632/oncotarget.19214. eCollection 2017 Sep 12. PubMed PMID: 29029452; PubMed Central PMCID: PMC5630352.

13: Sui A, Xu Y, Li Y, Hu Q, Wang Z, Zhang H, Yang J, Guo X, Zhao W. The pharmacological role of histone demethylase JMJD3 inhibitor GSK-J4 on glioma cells. Oncotarget. 2017 Aug 2;8(40):68591-68598. doi: 10.18632/oncotarget.19793. eCollection 2017 Sep 15. PubMed PMID: 28978140; PubMed Central PMCID: PMC5620280.

14: Morozov VM, Li Y, Clowers MM, Ishov AM. Inhibitor of H3K27 demethylase JMJD3/UTX GSK-J4 is a potential therapeutic option for castration resistant prostate cancer. Oncotarget. 2017 Jul 8;8(37):62131-62142. doi: 10.18632/oncotarget.19100. eCollection 2017 Sep 22. PubMed PMID: 28977932; PubMed Central PMCID: PMC5617492.

15: Inoue SI, Takahara S, Yoshikawa T, Niihori T, Yanai K, Matsubara Y, Aoki Y. Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice. Hum Mol Genet. 2017 Dec 1;26(23):4715-4727. doi: 10.1093/hmg/ddx354. PubMed PMID: 28973166.

16: Yan N, Xu L, Wu X, Zhang L, Fei X, Cao Y, Zhang F. GSKJ4, an H3K27me3 demethylase inhibitor, effectively suppresses the breast cancer stem cells. Exp Cell Res. 2017 Oct 15;359(2):405-414. doi: 10.1016/j.yexcr.2017.08.024. Epub 2017 Aug 18. PubMed PMID: 28823831.

17: Das A, Arifuzzaman S, Yoon T, Kim SH, Chai JC, Lee YS, Jung KH, Chai YG. RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor. Sci Rep. 2017 Jul 26;7(1):6554. doi: 10.1038/s41598-017-06914-5. PubMed PMID: 28747667; PubMed Central PMCID: PMC5529413.

18: Backe MB, Andersson JL, Bacos K, Christensen DP, Hansen JB, Dorosz JJ, Gajhede M, Dahlby T, Bysani M, Kristensen LH, Ling C, Olsen L, Mandrup-Poulsen T. Lysine demethylase inhibition protects pancreatic β cells from apoptosis and improves β-cell function. Mol Cell Endocrinol. 2018 Jan 15;460:47-56. doi: 10.1016/j.mce.2017.07.001. Epub 2017 Jul 4. PubMed PMID: 28684291.

19: Dalvi MP, Wang L, Zhong R, Kollipara RK, Park H, Bayo J, Yenerall P, Zhou Y, Timmons BC, Rodriguez-Canales J, Behrens C, Mino B, Villalobos P, Parra ER, Suraokar M, Pataer A, Swisher SG, Kalhor N, Bhanu NV, Garcia BA, Heymach JV, Coombes K, Xie Y, Girard L, Gazdar AF, Kittler R, Wistuba II, Minna JD, Martinez ED. Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors. Cell Rep. 2017 May 23;19(8):1669-1684. doi: 10.1016/j.celrep.2017.04.077. PubMed PMID: 28538184; PubMed Central PMCID: PMC5531293.

20: Ha SD, Cho W, Kim SO. HDAC8 Prevents Anthrax Lethal Toxin-induced Cell Cycle Arrest through Silencing PTEN in Human Monocytic THP-1 Cells. Toxins (Basel). 2017 May 16;9(5). pii: E162. doi: 10.3390/toxins9050162. PubMed PMID: 28509866; PubMed Central PMCID: PMC5450710.