The DOT1L, a kind of H3K79 methyltransferase, is another important histone-methylation regulator. DOT1L plays a role in several processes such as mixed-lineage leukemia gene (MLL)-rearranged leukemia, erythropoiesis, cardiac differentiation, embryonic development, cartilage homeostasis and chondrocyte differentiation by inducing H3K79 methylation. EPZ004777 HCl is a potent, selective DOT1L inhibitor with an IC50 of 0.4 nM in a cell-free assay. In in vitro, studies have demonstrated that EPZ004777 leads to a dose-dependent reduction in the global H3K79 dimethylation level, and has highest selective binding ability with DOT1L than other HMTs, including PRMT5. Of note, EPZ004777 is strikingly susceptive for the MLL-rearranged cell lines, such as MLL-AF9, MLL-AF10 and CALM-AF10 genes transformed murine bone hematopoietic cells at a dose of 3 μM or more greater, resulting in the cell cycle arrest, growth inhibition, differentiation and apoptosis. The number of MV4-11 and MOLM-13 cells, MLL-rearranged cell lines, is dramatically reduced by EPZ004777, whereas the growth of Jurkat cells is unaffected, further supported its high specificity. In in vivo, EPZ004777 HCl effective suppressed tumor growth in MLL leukemia xenograft mice and improved life expectancy. Moreover, mice exposure to EPZ004777 HCl daily for continuous 14 days significantly increase the total leucocytes in blood, mainly resulted from an increase in lymphocytes, monocytes and neutrophils. EPZ004777 is well tolerated and no overt toxicity is observed from 50-100 mg/mL. EPZ004777 (50, 100, or 150 mg/mL) administration is well tolerated, and no significant weight loss is observed, together with no significant weight loss.
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