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, 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.