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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MLL-AF10 and CALM-AF10 transformed LSK cells
10 µM
2 weeks
To test the effect of EPZ004777 on the colony forming ability, results showed significantly fewer compact colonies were formed.
Leukemia. 2013 Apr;27(4):813-22.
EPZ004777 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MLL-AF10 and CALM-AF10 transformed cells
Injection
10 µM
2 weeks
To assess the spleen-colony forming ability post-treatment, results showed that treated cells failed to form any large spleen colonies.
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