EPZ-5676

EPZ-5676 is a novel small molecule inhibitor of DOT1L. EPZ-5676 has an inhibition constant value of 80 pM, and demonstrates 37000-fold selectivity over all other methyltransferases tested. EPZ-5676 inhibits proliferation of MLL-AF4 rearranged cell line MV4-11 with an IC50 of 9 nM. EPZ-5676 reduces H3K79 dimethylation with a cellular IC50 of 2.6 nM in MV4-11 cells. EPZ-5676 blocks the activity of the histone lysine-methyltransferase DOT1L, thereby inhibiting H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is a potential treatment of MLL-rearranged leukemia and is under clinical investigation.