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EPZ-6438

现货
Catalog No.
A8221
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
20mg
¥ 1,250.00
现货
50mg
¥ 2,100.00
现货
100mg
¥ 3,600.00
现货

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Background

EPZ-6438 is a potent and bio-available inhibitor of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2) catalyzing the methylation of lysine 27 of histone H3 (H3K27), that inhibits the activity of human PRC2-containing wild-type EZH2 with a value of inhibition constant Ki of 2.5 nM. EPZ-6438 competitively binds to the S-adenosylmethionine (SAM) binding site of EZH2 and also non-competitively binds to the binding sites of peptide or nucleosome substrate. EPZ-6438 selectively inhibits EZH2 with selectivity 35-fold greater than EZH1. Study results have suggested that EPZ-6438 exhibits dramatic and permanent anti-tumor activity in MRT models through synergistic effects of EPZ-6438-mediated EZH2 inhibition on several cancer pathways.

Reference

Sarah K. Knutson1, Natalie M. Warholic, Tim J. Wigle, Christine R. Klaus, Christina J. Allain, Alejandra Raimondi, Margaret Porter Scott, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon, Roy M. Pollock, Kevin W. Kuntz, and Heike Keilhack. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 2013; 110(19): 7922-7927

文献引用

1. Anastassiia Vertii, Jianhong Ou, et al. "Two Contrasting Classes of Nucleolus-Associated Domains in Mouse Fibroblast Heterochromatin." bioRxiv. 2018 December 03.
2.Jiang S, Zhou H, et al. "The Epstein-Barr Virus Regulome in Lymphoblastoid Cells." Cell Host Microbe. 2017 Oct 11;22(4):561-573.e4. PMID:29024646
3. Arifuzzaman S, Das A, et al. "Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation." Biochem Pharmacol. 2017 Apr 19. pii: S0006-2952(17)30233-2. PMID:28431938
4. Wang H, Tian L, et al. "Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies." Nat Commun. 2017 Apr 21;8:15045. PMID:28429794
5. Xia B, Gerstin E, et al. "Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila." Aging (Albany NY). 2016 Nov 25;8(11):2988-3008. PMID:27889707

Chemical Properties

Physical AppearanceA solid
StorageDesiccate at -20°C
M.Wt572.74
Cas No.1403254-99-8
FormulaC34H44N4O4
SynonymsE-7438
Solubility≥28.637mg/mL in DMSO, <2.39 mg/mL in EtOH, <2.4 mg/mL in H2O
Chemical NameN-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide
SDFDownload SDF
Canonical SMILESCCN(C1CCOCC1)C2=CC(=CC(=C2C)C(=O)NCC3=C(C=C(NC3=O)C)C)C4=CC=C(C=C4)CN5CCOCC5
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

细胞实验: [1]

细胞系

SMARCB1确实MRT细胞

制备方法

溶解度有限。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

4-7天

实验结果

EPZ-6438以浓度依赖性方式降低总H3K27Me3含量。此外,EPZ-6438产生显著抗增殖作用,IC50值在纳摩尔范围内。EPZ-6438引起CD133、DOCK4和PTPRK的表达,并以时间依赖性方式上调CDKN1A、CDKN2A和BIN1的表达。

动物实验: [2]

动物模型

携带EZH2突变淋巴瘤异种移植物的SCID小鼠。

给药剂量

每8小时1次,每天3次,每12小时一次,一天2次或口服,每天一次,7或28天。

实验结果

EPZ-6438以剂量依赖性方式降低肿瘤H3K27Me3的水平,EC50为23 nmol/L。在给药七天/停药七天和给药21天/停药7天的2个周期中,EPZ-6438以剂量依赖性方式显示出显著的抗肿瘤作用,除了最低浓度,其余所有EPZ-6438剂量组引起完全的肿瘤消退。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

1. Knutson SK, Warholic NM, Wigle TJ et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7.

2. Knutson SK, Kawano S, Minoshima Y et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014 Apr;13(4):842-54.

生物活性

描述 EPZ-6438是一种有效的和选择性的EZH2抑制剂,Ki和IC50值分别为2.5 nM和11 nM。
靶点 EZH2          
IC50 11 nM (Ki=2.5 nM)          

质量控制

Chemical structure

EPZ-6438

相关生物数据

EPZ-6438

相关生物数据

EPZ-6438

相关生物数据

EPZ-6438

相关生物数据

EPZ-6438

相关生物数据

EPZ-6438