EPZ004777

SAM competitive inhibitor of DOT1L

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(1 ratings)

note: The Chemical Probes Portal only endorses compounds as chemical probes for use as specific and selective modulators of the proposed target if they receive three or more (3-4) stars.

Information

DOT1L

SAM competitive inhibitor

1 uM

DOI - 10.1016/j.ccr.2011.06.009

Probe Availability:

In Vitro Validations

Uniprot ID: Q8TEK3

Target Class: Epigenetic

Target SubClass: Protein methyltransferase

Potency: IC50

Potency Value: 0.4 nM

Potency Assay: DOT1L enzyme activity assay with PRC2

PDB ID for probe-target interaction (3D structure): --

Structure-activity relationship: Not available

Target aliases:

Histone-lysine N-methyltransferase, H3 lysine-79 s ...

DOI Reference: 10.1016/j.ccr.2011.06.009

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): EPZ004777 is >1,000-fold selective for DOT1L over other PMTs tested (CARM1, EHMT2, EZH1, EZH2, PRMT1, PRMT5, PRMT8, SETD7, WHSC1).

Probe Selectivity in Vitro:

Not available

Potency assay, off target (cells): PRMT5 (H4R3), PRDMs ((H3K9) and SMYDs (H3K4) protein substrates were not impacted in cells.

Probe Selectivity in Cell:

Not available

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

This DOT1L inhibitor was the first potent DOT1L ligand disclosed (by Epizyme) in 2011. EPZ004777 is an extremely potent and selective DOT1L inhibitor, making this an ideal probe for cellular use. The original publication shows that EPZ004777 effectively inhibits the proliferation of MLL-rearranged cell lines; however, due to restrictions of the pharmacokinetic properties of this molecule, whole animal studies needed to use subcutaneous osmotic pumps to attain useful compound exposure. Significant data on the non-epigenetic off-target profiling could not be found, and no closely related control compound is available.

(last updated: 21 Jan 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

EPZ004777 is an excellent probe for cellular experiments. It specifically affected the MLL-translocated leukemia lines that are dependent on DOT1L recruitment and enzymatic function. Due to the PK limitationsof EPZ004777, EPZ-5676 would be the best choice of DOT1L in vivo probe.

(last updated: 28 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

EPZ-5676, a derivative with a better pharmacokinetic profile than this probe, would be the better choice for a DOT1L chemical probe. EPZ-5676 is available commercially and is listed in the Portal. There are other derivatives which are better suited to in vivo model use.

(last updated: 27 Apr 2017 )