CAS 1373423-53-0|GSK-J4
| Common Name | GSK-J4 | ||
|---|---|---|---|
| CAS Number | 1373423-53-0 | Molecular Weight | 417.504 |
| Density | 1.2±0.1 g/cm3 | Boiling Point | 581.2±50.0 °C at 760 mmHg |
| Molecular Formula | C24H27N5O2 | Melting Point | / |
| MSDS | ChineseUSA | Flash Point | 305.3±30.1 °C |
Names
| Name | ethyl 3-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]propanoate |
|---|---|
| Synonym | More Synonyms |
GSK-J4 BiologicalActivity
| Description | GSK-J4 is a potent H3K27me3 histone lysine demethylase (KDM) inhibitor, with IC50s of 8.6 μM and 6.6 μM against KDM6B and KDM6A, respectively. |
|---|---|
| Related Catalog | Signaling Pathways >>Epigenetics >>Histone DemethylaseResearch Areas >>Cancer |
| Target | IC50: 8.6 µM (KDM6B), 6.6 µM (KDM6A)[5] |
| In Vitro | GSK-J4 has cellular activity in Flag-JMJD3-transfected HeLa cells, in which GSK-J4 prevents the JMJD3-induced loss of nuclear H3K27me3 immunostaining. Administration of GSK-J4 increases total nuclear H3K27me3 levels in untransfected cells. GSK-J4 significantly reduces the expression of 16 of 34 LPS-driven cytokines, including tumour-necrosis factor-α (TNF-α)[1]. GSK-J4 (10, 25 nM) acts upon DCs promoting the differentiation of Treg cells, improving Treg stability and suppressive capacities, without affecting the differentiation of Th1 and Th17 cells[2]. GSK-J4 inhibits the KDM6 family of H3K27me3 demethylases JMJD3 and UTX. GSK-J4 inhibits JMJD3 expression that is induced by TGF-β1[3]. GSK-J4 inhibits H3K4 demethylation at Xist, Nodal, and HoxC13 in female embryonic stem cells[4]. |
| In Vivo | 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[2]. |
| Animal Admin | Six-to eight-week-old female C57BL/6 WT mice are injected by subcutaneous injection (s.c.) with 50 μg myelin oligodendrocyte glycoprotein 35-55 peptide (pMOG) emulsified in Complete Freund's Adjuvant (CFA) supplemented with heat-inactivated Mycobacterium tuberculosis H37 RA. In addition, mice receive intraperitoneal injection (i.p.) of 500 ng of pertussis toxin on days 0 and 2. Clinical signs are assessed daily according to the following scoring criteria: 0, no detectable signs; 1, flaccid tail; 2, hind limb weakness or abnormal gait; 3, complete hind limb paralysis; 4, paralysis of fore and hind limbs; and 5, moribund or death. A stock solution of GSK-J4 of 42 mg/mL (100 mM) is prepared in dimethyl sulfoxide (DMSO) to preserve stability. Before injection, the stock solution is diluted 1/10 with ethanol (DMSO: ethanol, 1:10 v/v) and brought to a final concentration of 140 μg/mL in PBS. In systemic drug evaluation experiments, each mouse receive daily i.p. injections (from days 0-5) of 100 μL of this solution containing 14.0 μg of the GSK-J4 (equivalent to 0.56 mg/kg of the drug). Control mice receive 100 μL of the vehicle during the same period. In other EAE experiments, 106 bone marrow-derived DCs from WT mice are treated with GSK-J4 or vehicle alone for 16 h, pulsed with 5 μg/mL of pMOG for 4 h and then transferred i.v. into WT C57BL/6 recipient mice 14 and 7 days before EAE induction. In other adoptive transfer EAE experiments, CD4+Foxp3+ Treg cells generated in the presence or absence of 25 nM GSK-J4 are purified by cell sorting and then 0.75×106 transferred i.v. into WT C57BL/6 recipient mice 1 day before EAE induction. |
| 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]. 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. [3]. Yapp C, et al. H3K27me3 demethylases regulate in vitro chondrogenesis and chondrocyte activity in osteoarthritis. Arthritis Res Ther. 2016 Jul 7;18(1):158 [4]. 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 [5]. Heinemann B, et al. Inhibition of demethylases by GSK-J1/J4. Nature. 2014 Oct 2;514(7520):E1-2 [6]. 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. |
Chemical & Physical Properties
| Density | 1.2±0.1 g/cm3 |
|---|---|
| Boiling Point | 581.2±50.0 °C at 760 mmHg |
| Molecular Formula | C24H27N5O2 |
| Molecular Weight | 417.504 |
| Flash Point | 305.3±30.1 °C |
| Exact Mass | 417.216461 |
| PSA | 80.24000 |
| LogP | 3.75 |
| Appearance of Characters | white to beige |
| Vapour Pressure | 0.0±1.6 mmHg at 25°C |
| Index of Refraction | 1.615 |
| InChIKey | WBKCKEHGXNWYMO-UHFFFAOYSA-N |
| SMILES | CCOC(=O)CCNc1cc(N2CCc3ccccc3CC2)nc(-c2ccccn2)n1 |
| Storage condition | 2-8°C |
| Water Solubility | DMSO: soluble20mg/mL, clear |
Safety Information
| Hazard Codes | Xi |
|---|---|
| Risk Phrases | 36/37/38 |
| Safety Phrases | 26 |
| RIDADR | NONH for all modes of transport |
Articles6
More Articles| The TrxG Complex Mediates Cytokine Induced De Novo Enhancer Formation in Islets. PLoS ONE 10 , e0141470, (2015) To better understand how β-cells respond to proinflammatory cytokines we mapped the locations of histone 3 lysine 4 monomethylation (H3K4me1), a post-translational histone modification enriched at act... | |
| New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. Hum. Mol. Genet. 23(24) , 6553-66, (2014) Cardio-facio-cutaneous (CFC) syndrome is one of the 'RASopathies', a group of phenotypically overlapping syndromes caused by germline mutations that encode components of the RAS-MAPK pathway. Germline... | |
| Histone demethylation maintains Prdm14 and Tsix expression and represses xIst in embryonic stem cells. PLoS ONE 10 , e0125626, (2015) Epigenetic reprogramming is exemplified by the remarkable changes observed in cellular differentiation and X-chromosome inactivation (XCI) in mammalian female cells. Histone 3 lysine 27 trimethylation... |
Synonyms
| GSK-J4 |
| Ethyl N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-β-alaninate |
| GSK J4 HCl |
| β-Alanine, N-[2-(2-pyridinyl)-6-(1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl)-4-pyrimidinyl]-, ethyl ester |
