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Purity: ≥98%
GSK J4 is a novel, cell permeable, and potent prodrug of GSK J1, which is the first selective inhibitor of the H3K27 histone demethylase (KDM) JMJD3 and UTX with IC50 of 60 nM in a cell-free assay and is 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). GSK-J4 (0.5 mg/kg, i.p.) significantly reduces the severity and delays the onset of the disease of the mouse model of experimental autoimmune encephalomyelitis.
| ln Vitro |
In Flag-JMJD3-transfected HeLa cells, GSK-J4 exhibits cellular activity and inhibits the JMJD3-induced decrease of nuclear H3K27me3 immunostaining. In untransfected cells, administration of GSK-J4 raises total nuclear H3K27me3 levels. Tumor-necrosis factor-α (TNF-α) is one of the 16 LPS-driven cytokines that GSK-J4 dramatically lowers the expression of[1]. GSK-J4 (5 μM; 48 hours) increases the amount of H3K27me3 in mouse podocytes by more than three times. In cultured podocytes, GSK-J4 lowers the levels of Jagged-1 protein and mRNA while raising H3K27me3. Similarly, pretreatment with GSK-J4 inhibits the increase in intracellular N1-ICD levels, the increase in α-SMA, and the decrease in podocin mRNA levels in podocytes exposed to the dedifferentiation inducer TGF-β1[2]. Without influencing the differentiation of Th1 and Th17 cells, GSK-J4 (10, 25 nM) operates on DCs to enhance Treg cell development, stability, and suppressive abilities[3]. TGF-β1-induced JMJD3 expression is inhibited by GSK-J4[4]. In female embryonic stem cells, GSK-J4 inhibits H3K4 demethylation at Xist, Nodal, and HoxC13[5].
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| ln Vivo |
In diabetic mice, GSK-J4 Hydrochloride (10 mg/kg; ip; three times a week for ten weeks) reduces the progression of kidney disease[2]. GSK-J4 (0.5 mg/kg, ip) dramatically lessens the severity of experimental autoimmune encephalomyelitis in mice and postpones the onset of the disease[3].
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| Animal Protocol |
Animal/Disease Models: Eightweeks old male db/m and db/db mice[2]
Doses: 10 mg/kg Route of Administration: ip; thrice-weekly for 10 weeks Experimental Results: Attenuated the development of kidney disease in diabetic mice. |
| References |
[1]. Kruidenier L, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012 Aug 16;488(7411):404-8.
[2]. Majumder S, et al. Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease. J Clin Invest. 2018 Jan 2;128(1):483-499. [3]. Donas C, et al. The histone demethylase inhibitor GSK-J4 limits inflammation through the induction of a tolerogenic phenotype on DCs. J Autoimmun. 2016 Dec;75:105-117. [4]. Xuan Chu, et al. GSK-J4 induces cell cycle arrest and apoptosis via ER stress and the synergism between GSK-J4 and decitabine in acute myeloid leukemia KG-1a cells. Cancer Cell International volume 20, Article number: 209 (2020). [5]. Yapp C, et al. H3K27me3 demethylases regulate in vitro chondrogenesis and chondrocyte activity in osteoarthritis. Arthritis Res Ther. 2016 Jul 7;18(1):158 [6]. Kamikawa YF, et al. Histone demethylation maintains Prdm14 and Tsix expression and represses xIst in embryonic stem cells. PLoS One. 2015 May 20;10(5):e0125626 [7]. Heinemann B, et al. Inhibition of demethylases by GSK-J1/J4. Nature. 2014 Oct 2;514(7520):E1-2 |
| Molecular Formula |
C24H27N5O2
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| Molecular Weight |
417.5
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| CAS # |
1373423-53-0
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| Related CAS # |
GSK-J1;1373422-53-7;GSK-J2;1394854-52-4;GSK-J5;1394854-51-3;GSK-J4 hydrochloride;1797983-09-5;GSK-J1 lithium salt
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| SMILES |
O=C(OCC)CCNC1=NC(C2=NC=CC=C2)=NC(N3CCC4=CC=CC=C4CC3)=C1
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.98 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3952 mL | 11.9760 mL | 23.9521 mL | |
| 5 mM | 0.4790 mL | 2.3952 mL | 4.7904 mL | |
| 10 mM | 0.2395 mL | 1.1976 mL | 2.3952 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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