COMMENT EPZ-5676 (pinometostat) is a first-in-class inhibitor of DOT1L activity. EPZ-5676 is a potent and selective inhibitor of DOT1L with activity in both cellular and rodent MLL-models. Nonclinical in vivo pharmacokinetics of EPZ-5676 in mouse, rat and dog showed moderate to high clearance and low oral bioavailability, so sustained plasma exposures in rat require IV fusion. For cellular experiments, I recommend using EPZ-5676 in parallel with a second chemical probe SGC0946 to seek a consistent outcome, as both are potent inhibitors of DOT1L activity. The 'inactive control' SGC-0649 could also be used but only at relatively low concentrations because it still retains some DOT1L activity (IC50=390 nM). For in vivo PK-PD experiments, I recommend administering EPZ-5676 by continuous IV infusion to achieve sustained plasma levels above concentrations shown to be efficacious in cell models. Jun 30 2016 - 12:34am; EPZ-5676 continuous IV infusion for 21 days in a xenograft model of MLL-rearranged leukemia leads to dose-dependent anti-tumor activity. At the highest dose of 70.5 mg/kg/day, complete tumor regression is achieved with no regrowth for up to 32 days after the cessation of treatment. No significant weight loss or obvious toxicity is observed in rats treated with EPZ-5676 during an efficacy study. The selectivity of this agent (>37,000-fold selectivity against all other PMTs tested) makes it a useful cellular tool that is appropriate for rodent models. Jun 30 2016 - 4:19am

MOA Inhibitor (Chemical Probes.org)