EPZ004777

产品说明书

Print
Chemical Structure| 1338466-77-5 同义名 : -
CAS号 : 1338466-77-5
货号 : A162690
分子式 : C28H41N7O4
纯度 : 99%+
分子量 : 539.67
MDL号 : MFCD25563264
存储条件：

Pure form Keep in dark place, inert atmosphere, store in freezer, under -20°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 85 mg/mL(157.5 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
生物活性
靶点

  • Histone Methyltransferase

    DOT1L, IC50:0.4 nM
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
细胞系 浓度 检测类型 检测时间 活性说明 数据源
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
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.85mL

0.37mL

0.19mL

9.26mL

1.85mL

0.93mL

18.53mL

3.71mL

1.85mL
参考文献

[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.