CAS |
1797983-09-5 |
Chinese Name |
GSK-J4 盐酸盐 |
English Name |
GSK J4 Hydrochloride |
Synonyms |
;GSK-J4盐酸盐;GSK-J4HCl;GSKJ4HCl;GSK-J4hydrochloride; |
Molecular Formula |
C24H27N5O2·HCl |
Molecular Weight |
453.96 |
Solubility |
Soluble in DMSO |
Purity |
≥98% |
Appearance |
Light yellow to yellow Solid |
Storage |
Powder:2-8℃,2 years;Insolvent(Mother Liquid):-20℃,6 months;-80℃,1 year |
MDL |
MFCD26142638 |
SMILES |
O=C(OCC)CCNC1=NC(C2=CC=CC=N2)=NC(N3CCC(C=CC=C4)=C4CC3)=C1 |
InChIKey |
TYXWLTBYINKVNT-UHFFFAOYSA-N |
InChI |
InChI=1S/C24H27N5O2.ClH/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);1H |
PubChem CID |
71729974 |
Target Point |
Histone Demethylase |
Passage |
Epigenetics |
Background |
GSK J4 Hydrochloride is a potent dual inhibitor of H3K27me3/me2 demethylases JMJD3/KDM6B and UTX/KDM6A |
Biological Activity |
GSK-J4是一种有效的H3K27me3组蛋白赖氨酸脱甲基酶 (KDM) 抑制剂,抑制 KDM6B和KDM6A的 IC50 分别为8.6 μM 和 6.6 μM[1-6]。 |
IC50 |
8.6μM(KDM6B),6.6μM(KDM6A)[5] |
In Vitro |
GSK-J4抑制KK6家族的H3K27me3去甲基化酶JMJD3和UTX。 GSK-J4抑制由TGF-β1诱导的JMJD3表达[3]。GSK-J4在Flag-JMJD3转染的HeLa细胞中具有细胞活性,其中GSK-J4阻止JMJD3诱导的核H3K27me3免疫染色的丧失。施用GSK-J4增加未转染细胞中的总核H3K27me3水平。 GSK-J4显著降低了34种LPS驱动的细胞因子中16种的表达,包括肿瘤坏死因子-α(TNF-α)[1]。 GSK-J4(10,25 nM)作用于促进Treg细胞分化,改善Treg稳定性和抑制能力的DC,而不影响Th1和Th17细胞的分化[2]。 GSK-J4抑制雌性胚胎干细胞中Xist,Nodal和HoxC13的H3K4去甲基化[4]。 |
In Vivo |
GSK-J4(0.5 mg/kg,ip)可显著降低实验性自身免疫性脑脊髓炎小鼠模型的严重程度并延缓其发病[2]。 |
Animal Experiment |
6至8周龄的雌性C57BL/6 WT小鼠通过皮下注射(sc)注射50μg髓鞘少突胶质细胞糖蛋白35-55肽(pMOG),其在完全弗氏佐剂(CFA)中乳化,补充有热灭活的结核分枝杆菌H37 RA。此外,小鼠在第0天和第2天接受500ng百日咳毒素的腹膜内注射(ip)。根据以下评分标准每天评估临床体征:0,没有可检测的迹象; 1,松弛的尾巴; 2,后肢无力或步态异常; 3,完全后肢麻痹; 4,前肢和后肢麻痹; 5,垂死或死亡。在二甲基亚砜(DMSO)中制备GSK-J4的储备溶液42mg/mL(100mM)以保持稳定性。在注射之前,将储备溶液用乙醇(DMSO:乙醇,1:10v/v)稀释1/10并在PBS中达到140μg/ mL的终浓度。在全身药物评估实验中,每只小鼠每天接受100μL含有14.0μgGSK-J4(相当于0.56mg/kg药物)的该溶液的ip注射(从第0-5天开始)。对照小鼠在同一时期接受100μL载体。在其他EAE实验中,来自WT小鼠的106个骨髓来源的DC用GSK-J4或单独的载体处理16小时,用5μg/ mL的pMOG脉冲4小时,然后静脉内转移到WT C57BL/6受体小鼠14中。和EAE诱导前7天。在其他过继转移EAE实验中,在25nM GSK-J4存在或不存在下产生的CD4 + Foxp3 + Treg细胞通过细胞分选纯化,然后在EAE诱导前1天将0.75×106静脉内转移到WT C57BL/6受体小鼠中。 |
Data Literature Source |
[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. |
Unit |
Piece |
Specification |
10mg |