"目录号: HY-15227A
Epigenetics-
EPZ004777盐酸盐是高活性DOT1L抑制剂，IC50为0.4 nM。
Histone Methyltransferase
相关产品
EPZ-6438-GSK126-GSK343-3-Deazaneplanocin A hydrochloride-EPZ-5676-EPZ015666-UNC0642-UNC1999-BIX-01294-UNC0638-EPZ004777-EPZ031686-PFI-2 hydrochloride-A-366-SGC0946-
生物活性
Description
EPZ004777 hydrochloride is a potent, selectiveDOT1Linhibitor withIC50of 0.4 nM.
IC50& Target
IC50: 0.4 nM (DOT1L)[1]
In Vitro
EPZ004777 demonstrates potent, concentration-dependent inhibition of DOT1L enzyme activity with an IC50of 400±100 pM. EPZ004777 displays remarkable selectivity for inhibition of DOT1L over other HMTs(PRMT5, 521±137 nM; others, >50 μM). The effect of extended EPZ004777 treatment is remarkably specific for theMLL-rearranged cell lines. The number of viable MV4-11 and MOLM-13 cells is dramatically reduced by EPZ004777, whereas the growth of Jurkat cells is unaffected. A small population of MV4-11 cells remain viable in the presence of EPZ004777, but their number remain constant when growth curves are tracked over longer periods indicating that they have ceased to divide. The proliferation of MLL-AF9-transformed cells is strongly inhibited by EPZ004777 at concentrations of 3 μM or greater[1]. EPZ004777 selectively inhibits proliferation of MLL-AF10 and CALM-AF10 transformed murine bone marrow cells[2].
In Vivo
EPZ004777 is well tolerated and no overt toxicity is observed. Complete blood count analysis after 14 days of continuous exposure to EPZ004777 revealed a statistically significant increase in the total white blood cell count, which resulted from an increase in neutrophils, monocytes, and lymphocytes. EPZ004777 (50, 100, or 150 mg/mL) administration is well tolerated, and no significant weight loss is observed[1].
References
[1].Daigle SR, 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.
[2].Chen L, et al. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia. 2013 Apr;27(4):813-22.
[3].Deshpande AJ, et al. Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l.Blood. 2013 Mar 28;121(13):2533-41.