Pinometostat (EPZ5676) is an S-adenosyl methionine (SAM) competitive inhibitor of protein methyltransferase DOT1L with Ki of 80 pM in a cell-free assay, demonstrating >37,000-fold selectivity against all other PMTs tested, inhibits H3K79 methylation in tumor. Phase 1.
EPZ-5676 inhibits H3K79me2 with IC50 values of 3 nM and 5 nM in MV4-11 and HL60 cells, respectively. EPZ-5676 is a potent inhibitor of MV4-11 proliferation with an IC50 value of 3.5 nM. EPZ-5676 induces a synergistic and durable antiproliferative effect, increases expression of differentiation markers and apoptosis as dingle agent, and demonstrates combination benefit in combination with AML standard of care drugs in MLL-r cells.