DOT1L Inhibitor Program
EPZ-5676 is being developed as a personalized therapeutic for patients with
MLL-r leukemia, a genetically defined type of acute leukemia. EPZ-5676 is a
novel, potent and selective small molecule inhibitor of DOT1L. DOT1L is a
HMT that leads to the development of acute leukemia associated with
rearrangements of the MLL gene on chromosome 11. Rearrangements of MLL
result in the recruitment of DOT1L activityto aberrant gene locations, leading
to the expression of the leukemia-causing genes HOXA9 and MEIS1. EPZ-5676
was developed internally using Epizyme’s proprietary product platform.
Data published by Epizyme in Cancer Cell demonstrate that a DOT1L inhibitor selectively kills
MLL-r cells while sparing cells that do not contain the MLL-r genetic
alteration, significantly extending survival in animal models of MLL-r.
EPZ-5676 is the first HMTi to enter human clinical development.
About MLL-r Leukemia
MLL-r leukemia is a group of acute leukemias (either of myeloid, lymphoid, or mixed lineage) that affects adults, infants, and children. They share a common causative abnormality: rearrangements of the MLL gene, located on chromosome 11. These rearrangements are detected by current standard diagnostic tests. The DOT1L HMT, as described above, is directly implicated in the development of these leukemias, by promoting the expression of leukemia-causing genes. Though representing a range of clinical presentations, the prognosis of this group of leukemias is uniformly poor. Current standard chemotherapy is non-specific and toxic, rather than being targeted specifically towards theaberrant DOT1L activity that drives this group of leukemias. More specific and effective therapies are needed for patients with MLL-r leukemia.