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GSK343

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Catalog No.
A3449
EZH2抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 750.00
现货
5mg
¥ 600.00
现货
10mg
¥ 1,000.00
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25mg
¥ 1,900.00
现货

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Background

GSK343 is a selective and SAM-competitive inhibitor of the histone lysine methyltransferase EZH2 with IC50 value of 4 nM [1].

EZH2 (enhancer of zestehomolog 2) is a catalytic subunit of the protein complex (polycomb repressive complex 2, PRC2). It catalyzes the methylation of H3K27 through transferring the methyl group of SAM to H3K27. The trimethylation of H3K27 subsequently results in the transcription suppression of target genes such as RUNX3, FOXC1 and BRCA1. The overexpression and mutation of EZH2 have been found in many sorts of tumors demonstrating that EZH2 is an attractive target for the treatment of cancers. As a potent EZH2 inhibitor, GSK343 inhibits the activity of the enzyme via competing with the cofactor SAM [1, 2].

GSK343 is a selective EZH2 inhibitor. It showed no significant inhibitory effects on other enzymes requiring SAM as cofactor, including DNMT, MLL, PRMT and SETMAR. GSK343 exerted a certain degree of effective on EZH1 with IC50 value of 240 nM since EZH1 was quite homologous to EZH2. In cultured HCC1806 breast cancer cells, treatment of GSK343 dose-dependently reduced H3K27me3 with IC50 value of 174 nM. Besides that, GSK343 was found to inhibit cell proliferation in some breast and prostate cancer cells. In LNCaP cells, GSK343 suppressed cell growth with IC50 value of 2.9 μM. In human EOC cells, GSK343 notably inhibited cell invasion and induced cell apoptosis. GSK343 was also found to induce LC3-II accumulation and autophagy in A549, MDA-MB-231 and HepG2 cell. It enhanced the antitumor activity of sorafenib which was a multikinase inhibitor and could decrease the expression of EZH2 in HepG2 cells [1, 3 and 4].

GSK343 is only used as a tool to investigate EZH2 in vitro because of its high clearance in the animal model [1].

References:
[1] Verma S K, Tian X, LaFrance L V, et al.  Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS medicinal chemistry letters, 2012, 3(12): 1091-1096.
[2] Ferraro A, Boni T, Pintzas A.  EZH2 Regulates Cofilin Activity and Colon Cancer Cell Migration by Targeting ITGA2 Gene. PloS one, 2014, 9(12): e115276.
[3] Amatangelo M, Garipov A, Li H, et al.  Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition. Cell Cycle, 2013, 12(13): 2113-2119.
[4] Liu T P, Lo H L, Wei L S, et al.  S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells. Anti-cancer drugs, 2015, 26(2): 139.

文献引用

1. Ihira K, Dong P, et al. "EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis." Oncotarget. 2017 Feb 21;8(8):13509-13520. PMID:28088786

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt541.69
Cas No.1346704-33-3
FormulaC31H39N7O2
SynonymsGSK-343;GSK 343
Solubility≥7.58 mg/mL in DMF with gentle warming, <2.45 mg/mL in EtOH, <2.09 mg/mL in H2O
Chemical NameN-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-6-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1-propan-2-ylindazole-4-carboxamide
SDFDownload SDF
Canonical SMILESCCCC1=C(C(=O)NC(=C1)C)CNC(=O)C2=C3C=NN(C3=CC(=C2)C4=CC(=NC=C4)N5CCN(CC5)C)C(C)C
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

体外抗组蛋白甲基转移酶生化试验

使用含5种成分的PRC2复合物(Flag-EZH2、EED、SUZ12、AEBP2和RbAp48)测定抗EZH2的活性。实验方案概括如下:使化合物固体溶于100% DMSO中,制备10 mM原液。在384孔板中,准备用于11次连续稀释的主板(以1:3比例稀释,柱6和18与DMSO对照组具有相同的体积),使用声控分配技术将稀释液分装到即用的分析板上,以制备100 nL化合物与DMSO对照液样本。使用多点结合分配将含等体积的10 nM EZH2和底物溶液((5 ?g/mL HeLa核小体和0.25 ?M [3H]-SAM)加入到分析板中。将反应板孵育1小时后,使用等体积的0.5 mg/mL PS-PEI Imaging Beads (RPNQ0098) (含0.1 mM未标记的SAM)进行淬灭。将平板密封,使其置于暗处,放置30分钟。在第5分钟,通过Viewlux成像仪获得其发光图像。通过Activity BaseXE对统计数据,如Z’和背景信号,以及剂量反应曲线进行分析。使用384孔SPA实验(与EZH2相同),以EZH1作为含5种成分的PRC2复合物的一部分,对其体外生物活性进行分析。对于EZH1和EZH2,缓冲液成分、试剂分配、化合物制备、淬灭条件以及数据分析均相同,最终测试浓度为20 nM EZH1,5 μM/mL HeLa 核小体以及0.25 μM [3H]-SAM。使用TIBCO Spotfire对pIC50和可视化图像进行进一步的数据分析。将化合物的结果记录在Reaction Biology Corp. (Malvern, PA) 上,以评估它们在组蛋白甲基转移酶试验中的抑制作用。通过HotSpot技术和以微型放射性同位素为基础的滤膜结合测定法分析甲基转移酶的活性。将抑制剂溶解于二甲基亚砜 (DMSO) 中,其测试浓度达100 uM,最终DMSO浓度为2%。将缓冲液(含指定浓度的甲基转移酶以及相应的底物(请见附表))与化合物一起预孵育10分钟。加入1μM S-腺苷-L-[甲基-3H]甲硫氨酸(SAM)启动反应,将其置于30℃下,孵育60分钟,随后将其转移到P81滤纸,使用PBS清洗,检测。

细胞实验 [1]:

细胞系

乳腺癌细胞系(HCC1806、Sk-Br-3和ZR-75-1)以及前列腺癌细胞系(DU145、PC3和LNCaP)

制备方法

在DMSO中的溶解度受限。若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

~ 50 μM;6天

实验结果

在HCC1806肺癌细胞中,GSK343抑制H3K27 (H3K27me3)三甲基化,其IC50值为174 nM。在乳腺癌细胞和前列腺癌细胞中,GSK343有效抑制细胞增殖。此外,前列腺癌细胞系LNCaP对GSK343最敏感,其IC50值为2.9 μM。

References:

[1]. Verma S K, Tian X, LaFrance L V, et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS medicinal chemistry letters, 2012, 3(12): 1091-1096.

生物活性

描述 GSK343是一种细胞通透性的EZH2抑制剂,IC50值为4 nM。
靶点 EZH2          
IC50 4 nM          

质量控制

化学结构

GSK343

相关生物数据

GSK343