Preclinical Pharmacokinetics and Pharmacodynamics of Pinometostat (EPZ-5676), a First-in-Class, Small Molecule S-Adenosyl Methionine Competitive Inhibitor of DOT1L.

Acute leukemias bearing mixed lineage leukemia (MLL) rearrangements are aggressive diseases characterized by a poor overall prognosis despite multi-agent chemotherapy. Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) lead to recruitment of DOT1L, to a multi-protein complex resulting in aberrant methylation of histone H3 lysine 79 at MLL target genes, and ultimately enhanced expression of critical genes for hematopoietic differentiation, including HOXA9 and MEIS1, and as such defines the established mechanism for leukemogenesis in MLL-rearrangement (MLL-r) leukemias. Pinometostat is a first-in-class, small molecule inhibitor of DOT1L with sub-nanomolar affinity and >37,000 fold selectivity against non-MLL HMTs, and was the first member of the novel HMT inhibitor class to enter Phase 1 clinical trials in both adult and pediatric MLL-r leukemia patients. In this article, the preclinical pharmacokinetics/pharmacodynamics and drug disposition of pinometostat are reviewed including discussion of how these data were used to inform early clinical studies, and how they translated to the clinical experience.