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EPZ5676

现货
Catalog No.
A4166
DOT1L抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,750.00
现货
10mg
¥ 1,700.00
现货
50mg
¥ 5,900.00
现货

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Background

EPZ5676 is a potent inhibitor of DOT1L histone methyltransferase, according to X-ray crystallographic analysis, that occupies the S-adenosyl methionine (SAM) binding pocket of DOT1L and induces conformational changes in DOT1L resulting in the opening of a hydrophobic pocket beyond the amino acid portion of SAM. EPZ5676 selectively inhibits DOTIL with a value of 50% inhibition concentration IC50 of 0.8 nM, which is 37000-fold greater in selectivity than other methyltransferases, including CARM1, EHMT1/2, EZH1/2, PRMT1/2/5/6/8, SETD7, SMYD2/3, and WHSC1/1L1. EPZ5676 has been investigated for the treatment of MLL-rearranged leukemia in multiple studies where results have shown that EPZ5676 inhibits H3K79 methylation and the expression of MLL-fusion target gene and potently kills acute leukemia cell lines bearing MLL translocation.

Reference

Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, Waters NJ, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 Aug 8;122(6):1017-1025.

文献引用

1. Kim MS, Cho HI, et al. "JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/β-Catenin Signaling Pathway." Sci Rep. 2018 Apr 26;8(1):6611. PMID:29700375

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt562.71
Cas No.1380288-87-8
FormulaC30H42N8O3
Solubility≥28.15 mg/mL in DMSO, ≥50.3 mg/mL in EtOH with ultrasonic, <2.42 mg/mL in H2O
Chemical Name(2R,3S,4S,5R)-2-(6-aminopurin-9-yl)-5-[[[3-[2-(6-tert-butyl-1H-benzimidazol-2-yl)ethyl]cyclobutyl]-propan-2-ylamino]methyl]oxolane-3,4-diol
SDFDownload SDF
Canonical SMILESCC(C)N(CC1C(C(C(O1)N2C=NC3=C2N=CN=C3N)O)O)C4CC(C4)CCC5=NC6=C(N5)C=C(C=C6)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]:

酶抑制试验

将抑制数据拟合到Morrison二次方程,计算EPZ5676酶抑制常数(Ki值)。通过表面等离子共振测定EPZ5676停留时间。EPZ5676停留时间为酶-配体解离速率的倒数,。

细胞实验 [1]:

细胞系

MV4-11细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C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 °C可放置数月。

反应条件

0.0005 ~ 10 μM;14天

实验结果

EPZ5676有效抑制MV4-11细胞增殖,其IC50值为3.5 nM。于EPZ5676治疗后的第4天,EPZ-5676开始显示出抗增殖活性。于EPZ-5676治疗后的第7天,其抗增殖活性最显著。

动物实验 [1]:

动物模型

携带MV4-11异种移植瘤的裸鼠

给药剂量

35、67或70 mg/kg/day;静脉注射;持续21天

实验结果

在携带MV4-11异种移植瘤的裸鼠中,EPZ5676使肿瘤完全消退。即使停止给药,其作用仍能持续一段时间。EPZ5676不会引起显著的体重减轻或毒性。

其它注意事项

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]. Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, Waters NJ, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013 Aug 8;122(6):1017-1025.

生物活性

描述 EPZ5676是一种有效的和选择性的DOT1L甲基转移酶抑制剂,Ki值为80 pM。
靶点 DOT1L          
IC50 80 pM (Ki)          

质量控制