GSK-J4 HCl | CAS#1797983-09-5 | 1373423-53-0 | Histone demethylase Inhibitor

MedKoo Cat#: 522432 | Name: GSK-J4 HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

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

GSK-J4 HCl

CAS#1797983-09-5 (HCl)

Theoretical Analysis

MedKoo Cat#: 522432

Name: GSK-J4 HCl

CAS#: 1797983-09-5 (HCl)

Chemical Formula: C24H28ClN5O2

Exact Mass: 0.0000

Molecular Weight: 453.97

Elemental Analysis: C, 63.50; H, 6.22; Cl, 7.81; N, 15.43; O, 7.05

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,650.00	Ready to ship
2g	USD 6,450.00	2 weeks

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Related CAS #

1797983-09-5 (HCl) 1373423-53-0 (free base)

Synonym

GSK-J4 HCl; GSK J4 HCl; GSK-J4 hydrochloride.

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 hydrochloride

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

Yellow 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

More Info

Related CAS# CAS#1797983-09-5 ( GSK-J4 hydrochloride) CAS#1373423-53-0 ( GSK-J4 free base)

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A9T01K28

QC Data

View QC data: current batch, Lot#A9T01K28

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

GSK-J4 hydrochloride 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 hydrochloride also inhibits LPS-induced TNF-α production in human primary macrophages with an IC50 of 9 μM.

In vitro activity:

To further analyze the role of histone demethylase KDM6B inhibitor GSK-J4 on ESCC cells. KEYS150 cell was treated with the indicated concentrations of GSK-J4(1,2.5, 5 μM). The results showed that KDM6B expression was significantly down-regulated (Fig. 7a, Sup Fig. 3E), and H3K27me3 expression was significantly up-regulated. CCK8 assay showed that treatment of KYSE150 with GSK-J4 inhibits relative cell viability compared with DMSO control at 96 h (Fig. 7b), as expected, treat with GSK-J4 significantly decreased the clone formation ability of KYSE150 cells, and treat with GSK-J4 markedly induced G1/S cell cycle arrest in KYSE150 cells (Fig. 7c,d). These results show that GSK-J4 Induces a Block in the G1 Phase of the Cell Cycle, inhibits the proliferation and Clone formation of ESCC cells. Reference: BMC Cancer. 2021; 21: 559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130268/

In vivo activity:

To further describe the anti-fibrotic action of JMJD3 and further demonstrate its influence on renal function, this study created a murine model of SNx and then treated mice with GSKJ4 for 4 weeks, starting at 4 weeks after SNx (Figure 2A). As shown in Figure 2B-C, serum Scr and BUN levels were higher in the SNx group than in the sham-operated group. GSKJ4 administration resulted in a further worsening of renal function in the SNx group. However, this treatment did not change the blood levels of Scr and BUN in the sham-operated mice. In line with the effect of GSKJ4 on renal function, GSKJ4 also caused the expansion of fibrotic areas as indicated by Masson trichrome staining (Figure 2D-E) and induced a more pronounced expression of α-SMA, fibronectin and collagen III in the remnant kidney of mice relative to mice treated with vehicle (Figure 2F-I). Correspondingly, GSKJ4 treatment significantly reduced JMJD3, and increased H3K27me3 expression levels in SNx kidneys. Reference: Theranostics. 2021; 11(6): 2706–2721. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806480/

	Solvent	mg/mL	mM
Solubility
	DMSO	60.8	134.00
	DMSO:PBS (pH 7.2) (1:7)	0.1	0.22
	DMF	30.0	66.08
	Ethanol	55.0	121.15
	Water	10.0	22.03

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 453.97 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. Qin M, Han F, Wu J, Gao FX, Li Y, Yan DX, He XM, Long Y, Tang XP, Ren DL, Gao Y, Dai TY. KDM6B promotes ESCC cell proliferation and metastasis by facilitating C/EBPβ transcription. BMC Cancer. 2021 May 17;21(1):559. doi: 10.1186/s12885-021-08282-w. PMID: 34001062; PMCID: PMC8130268. 2. Kitajima S, Sun W, Lee KL, Ho JC, Oyadomari S, Okamoto T, Masai H, Poellinger L, Kato H. A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition. Sci Rep. 2021 Feb 25;11(1):4538. doi: 10.1038/s41598-021-83857-y. PMID: 33633164; PMCID: PMC7907191. 3. Yu C, Xiong C, Tang J, Hou X, Liu N, Bayliss G, Zhuang S. Histone demethylase JMJD3 protects against renal fibrosis by suppressing TGFβ and Notch signaling and preserving PTEN expression. Theranostics. 2021 Jan 1;11(6):2706-2721. doi: 10.7150/thno.48679. PMID: 33456568; PMCID: PMC7806480. 4. Doñas C, Neira J, Osorio-Barrios F, Carrasco M, Fernández D, Prado C, Loyola A, Pacheco R, Rosemblatt M. The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells. Sci Rep. 2021 Jan 14;11(1):1342. doi: 10.1038/s41598-020-79122-3. PMID: 33446666; PMCID: PMC7809056.

In vitro protocol:

In vivo protocol:

1. Yu C, Xiong C, Tang J, Hou X, Liu N, Bayliss G, Zhuang S. Histone demethylase JMJD3 protects against renal fibrosis by suppressing TGFβ and Notch signaling and preserving PTEN expression. Theranostics. 2021 Jan 1;11(6):2706-2721. doi: 10.7150/thno.48679. PMID: 33456568; PMCID: PMC7806480. 2. Doñas C, Neira J, Osorio-Barrios F, Carrasco M, Fernández D, Prado C, Loyola A, Pacheco R, Rosemblatt M. The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells. Sci Rep. 2021 Jan 14;11(1):1342. doi: 10.1038/s41598-020-79122-3. PMID: 33446666; PMCID: PMC7809056.

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.