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.
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]
EPZ004777 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human MCF10A cells
Function assay
Inhibition of DOT1L in human MCF10A cells assessed as reduction of H3K79 level， IC50=84 nM
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human MLL cells
Function assay
Inhibition of Hoxa9 and Meis1 gene expression in human MLL cells
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human MOLM13 cells
Proliferation assay
Antiproliferative activity against human MOLM13 cells containing MLL-AF9, EC50=4 nM
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human MV4-11 cells
Proliferation assay
Antiproliferative activity against human MV4-11 cells containing MLL-AF4, EC50=4 nM
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