EPZ-5676

Inhibitor of DOT1L

Structure

Information

Protein target names: DOT1L

Mechanism of action: Inhibitor

Recommended in-cell concentration:
Up to 100 nM

In Vitro Validations

Uniprot ID: Q8TEK3
Target Class:
Target SubClass: Protein methyltransferase
Potency: Ki
Potency Value: 0.08 nM
Potency Assay: SAM competition assay
PDB ID for probe-target interaction (3D structure): 4HRA
Target aliases:
Histone-lysine N-methyltransferase, H3 lysine-79 s ...

DOI Reference: 10.1182/blood-2013-04-497644

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

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.

(last updated: 17 Jun 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

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.

(last updated: 24 Jun 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 2 Jun 2017 )