Potent inhibition of DOT1L as treatment for MLL-fusion leukemia

Scott R. Daigle, Edward J. Olhava, Carly A. Therkelsen, Aravind Basavapathruni, Lei Jin, P. Ann Boriack-Sjodin, Christina J. Allain, Christine R. Klaus, Alejandra Raimondi, Margaret Porter Scott, Nigel J. Waters, Richard Chesworth, Mikel P. Moyer, Robert A. Copeland, Victoria M. Richon and Roy M. Pollock

Key points

  • EPZ-5676 is a potent DOT1L inhibitor that causes tumor regressions in a rat xenograft model of MLL-rearranged leukemia


Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness and there is thus a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has a Ki value of 80 pM, and demonstrates 37,000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous intravenous (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 therefore a potential treatment for MLL-rearranged leukemia and is currently under clinical investigation.

  • Submitted April 17, 2013.
  • Accepted May 23, 2013.