Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor

SummaryMislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL.

► A potent and selective inhibitor of DOT1L enzymatic activity has been designed ► The inhibitor blocks H3K79 methylation and selectively kills MLL-rearranged cells ► The inhibitor demonstrates antileukemia activity in a xenograft model of MLL ► These data validate the use of DOT1L inhibitors as targeted therapeutics for MLL