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CAS No.: 1338466-77-5

EPZ004777 Catalog No. CSN13673

Synonyms: EPZ004777

EPZ004777 is a potent, selective DOT1L inhibitor with IC50 of 0.4 nM in a cell-free assay and demonstrates > 1,200-fold selectivity for DOT1L over all other tested PMTs.

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 DOT1L

IC50:0.4nM
描述EPZ004777 is the first S-adenosylmethionine-competitive inhibitor of a protein methyltransferase with in vivo efficacy, exhibiting inhibitory effect on DOT1L with extraordinary potency in a radionuclide homogeneous assay (IC50 value of 0.4nM). EPZ004777 depleted H3K79me2 at 10μM post 48h in MV4;11 leukaemia cells expressing an MLL/AF4 fusion protein. It led time- and dose-dependent reductions in the H3K79me2 mark in the Molm13 MLL cell line that has the MLL/AF9 translocation^[3]. Accompanied with the inhibition of H3K79 methylation, time- and dose-dependent decrease of HOXA9 and MEIS1 on mRNA level could be observed in MV4-11 and MOLM-13 cells. EPZ004777 selectively inhibited proliferation of MLL-rearranged cell lines and MLL-AF9-transformed murine hematopoietic cells with IC50 values ranging in 0.17-6.47μM, and caused apoptosis and differentiation in MLL-rearranged cell lines. Administration of EPZ004777 through implanted pumps loaded with compound at concentrations of 50, 100, or 150mg/ml significantly increased median survival of mice model of MLL in a dose-dependent manner^[4].
作用机制EPZ004777 binds to the SAM-binding pocket of DOT1L.^[3]
细胞研究

Cell Data

Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
human MCF10A cells	-	Function assay	-	Inhibition of DOT1L in human MCF10A cells assessed as reduction of H3K79 level， IC50=84 nM	25406853
human MLL cells	-	Function assay	-	Inhibition of Hoxa9 and Meis1 gene expression in human MLL cells	23879463
human MOLM13 cells	-	Proliferation assay	-	Antiproliferative activity against human MOLM13 cells containing MLL-AF9, EC50=4 nM	23879463

更多
动物研究
剂量
Mice: 50 mg/ml - 150 mg/ml 21741596 (osmotic pumps), 10 mg/kg^[3] (i.v.)

给药途径
Osmotic pumps, i.v.
参考文献

动物研究
剂量	Mice: 50 mg/ml - 150 mg/ml 21741596 (osmotic pumps), 10 mg/kg^[3] (i.v.)
给药途径	Osmotic pumps, i.v.

[1] Yu W, Chory EJ, et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288.
[2] Daigle SR, Olhava EJ, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011 Jul 12;20(1):53-65.
[3] Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, Marineau JJ, Qi J, Barsyte-Lovejoy D, Yi J, Marcellus R, Iacob RE, Engen JR, Griffin C, Aman A, Wienholds E, Li F, Pineda J, Estiu G, Shatseva T, Hajian T, Al-Awar R, Dick JE, Vedadi M, Brown PJ, Arrowsmith CH, Bradner JE, Schapira M. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288. doi: 10.1038/ncomms2304. Erratum in: Nat Commun. 2013;4:1893. PMID: 23250418.
[4] Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, Jin L, Kuntz KW, Chesworth R, Moyer MP, Bernt KM, Tseng JC, Kung AL, Armstrong SA, Copeland RA, Richon VM, Pollock RM. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011 Jul 12;20(1):53-65. doi: 10.1016/j.ccr.2011.06.009. PMID: 21741596; PMCID: PMC4046888.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.8530 mL
- 9.2649 mL
- 18.5298 mL
- 5 mM
- 0.3706 mL
- 1.8530 mL
- 3.7060 mL
- 10 mM
- 0.1853 mL
- 0.9265 mL
- 1.8530 mL

技术信息

CAS号

1338466-77-5

储存条件

粉末: Keep in dark place,Inert atmosphere,Store in freezer, under -20°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C28H41N7O4

运输

蓝冰

分子量

539.67

别名

EPZ004777

溶解度

DMSO	88.0 mg/mL (163.1 mM)
Ethanol	86.0 mg/mL (159.4 mM)

动物实验配方

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