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GSK126

现货
Catalog No.
A3446
EZH2抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 840.00
现货
10mg
¥ 1,250.00
现货
50mg
¥ 2,900.00
现货
100mg
¥ 4,000.00
现货

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Background

GSK126 is an inhibitor of EZH2 with Ki Value of 93 pM [1].

Over-expression of EZH2 has been reported to be correlated with cancer progression and poor prognosis, high grade and high stage in several tumor types. GSK126 is a potent inhibitor of EZH2 and its functional residence time on activated form of EZH2/PRC2 is mush longer than unactivated forms [1]. When tested with lymphoma cell lines, results showed that harboring EZH2 mutations such as Y641N, Y641F or A677G were more sensitivity [2]. In DMS53, Lu30, H209 SCLC cells, cellular growth was inhibited with 0.5, 2, and 8μM GSK126 treatment [3]. And GSK126 could also significantly restore ARNTL expression in ovarian cancer cells thus inhibit cell growth and enhance chemosensitivity of cisplatin [4].

Intermittent dosing of GSK126 treated subcutaneous KARPAS-422 xenografts model could effectively inhibit its growth with or without a 1 week drug holiday. In mouse model with EZH2 mutant DLBCL xenografts, treatment with GSK126 could markedly inhibit its growth [2].

References:
1. Sato, T., et al., PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer. Sci Rep, 2013. 3(1911).
2. McCabe, M.T., et al., EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature, 2012. 492(7427): p. 108-12.
3. Van Aller, G.S., et al., Long residence time inhibition of EZH2 in activated polycomb repressive complex 2. ACS Chem Biol, 2014. 9(3): p. 622-9.
4. Yeh, C.M., et al., Epigenetic silencing of ARNTL, a circadian gene and potential tumor suppressor in ovarian cancer. Int J Oncol, 2014. 45(5): p. 2101-7.

文献引用

1. Liu Y, Niu Y, et al. "Tat expression led to increased histone 3 tri-methylation at lysine 27 and contributed to HIV latency in astrocytes through regulation of MeCP2 and Ezh2 expression." J Neurovirol. 2019 Apr 24. PMID:31020497
2. Hübner JM, Müller T, et al. "EZHIP / CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma." Neuro Oncol. 2019 Mar 29. pii: noz058. PMID:30923826
3. Anastassiia Vertii, Jianhong Ou, et al. "Two Contrasting Classes of Nucleolus-Associated Domains in Mouse Fibroblast Heterochromatin." bioRxiv. 2018 December 03.
4. Agnieszka I. Laskowski, Danielle A. Fanslow1,et al. "Clinical Epigenetic Therapies Disrupt Sex Chromosome Dosage Compensation in Human Female Cells." Gender and the Genome 2018, Vol. 2(1) 2-7
5. Jalan-Sakrikar N, De Assuncao TM, et al. "Hedgehog Signaling Overcomes an EZH2-Dependent Epigenetic Barrier to Promote Cholangiocyte Expansion." PLoS One. 2016 Dec 9;11(12):e0168266. PMID:27936185

Chemical Properties

StorageStore at -20°C
M.Wt526.67
Cas No.1346574-57-9
FormulaC31H38N6O2
SynonymsEZH2 inhibitor;GSK-126;GSK 126
Solubility≥3.29 mg/mL in DMSO, <2.4 mg/mL in EtOH, <2.27 mg/mL in H2O
Chemical Name1-[(2S)-butan-2-yl]-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-(6-piperazin-1-ylpyridin-3-yl)indole-4-carboxamide
SDFDownload SDF
Canonical SMILESCCC(C)N1C=C(C2=C(C=C(C=C21)C3=CN=C(C=C3)N4CCNCC4)C(=O)NCC5=C(C=C(NC5=O)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]:

抑制活性

使用含有野生型或突变体EZH2的五种PRC2复合体(人Flag-EZH2、EED、SUZ12、AEBP2和RbAp48)以及[3H]-SAM和组蛋白H3肽(21-44)进行生化测定,K27me0、K27me1或K27me2作为反应底物,将反应孵育30分钟。使用针对总组蛋白histoneH3、H3K27me1、H3K27me2或H3K27me3的特异性抗体,通过酶联免疫吸附测定(ELISA)或western印迹方法测定总体组蛋白修饰水平。

细胞实验[2]:

细胞系

Lu130、H209和 DMS53小细胞癌细胞系(SCLC)

溶解方法

溶于DMSO。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

0.、2和8 μM;72、144、192 h.

实验结果

在所测定的三种细胞系中,8 μM浓度的GSK126抑制细胞生长。

动物实验[1]:

动物模型

皮下异种移植KARPAS-422和Pfeiffer细胞的小鼠。

剂量

15、50,、150 mg/kg, 每天一次,连续10天;300 mg/kg,每周两次;腹腔内给药

实验结果

GSK126以剂量依赖性的方式降低H3K27me3并增加基因表达。50 mg/kg的GSK126完全抑制肿瘤生长,增加携带侵袭性KARPAS-422肿瘤的小鼠存活。GSK126所测量的剂量耐受性良好,测量过程中没有体重减轻现象。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1]. McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature, 2012, 492(7427): 108-112.

[2]. Sato T, Kaneda A, Tsuji S, et al. PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer. Sci Rep, 2013, 3: 1911.

质量控制

化学结构

GSK126

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