DOT1L inhibitor EPZ-5676 synergizes with cytarabine and azacitidine in preclinical models of MLL-rearranged leukemia

摘要: EPZ-5676 is a small molecule inhibitor of the histone methyltransferase DOT1L currently in clinical development and represents a first in class novel therapeutic agent for the treatment of MLL-rearranged (MLL-r) leukemia. In preclinical studies, EPZ-5676 selectively inhibited intracellular histone H3K79 methylation, downstream target gene expression and demonstrated complete tumor regression in a MLL-r leukemia xenograft model. We previously reported synergistic and durable anti-proliferative activity when EPZ-5676 was combined with current AML standard of care drugs, cytarabine and daunorubicin in MLL-r leukemia models MOLM-13 (MLL-AF9) and MV4-11 (MLL-AF4). Combination benefit was also observed when MLL-r cells were treated with cytarabine, prior to co-treatment with EPZ-5676. Additionally, both cytarabine and the DNA methyltransferase inhibitor azacitidine, displayed synergistic anti …