Peptide substrate competitive inhibitor, SAM noncompetitive inhibitor of EHMT2, EHMT1



Protein target names: EHMT2, EHMT1

Mechanism of action: Peptide substrate competitive inhibitor, SAM noncompetitive inhibitor

Primary References:

In Vitro Validations

Uniprot ID: Q96KQ7
Target Class: Epigenetic
Target SubClass: Protein methyltransferase
Potency: Ki
Potency Value: 3.7 nM
Potency Assay: Enzymatic activity assays.
PDB ID for probe-target interaction (3D structure): --
Structure-activity relationship: Yes
Target aliases:
Histone-lysine N-methyltransferase EHMT2, NG36, KM ...

DOI Reference: 10.1021/jm401480r

In Cell Validations

In Vivo Data

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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

UNC0642 potently and specifically inhibits G9a and GLP compared with a wide range of pharmacologically important proteins (except for the histamine H3 receptor) in cell-free assays. Importantly, the compound shows clear concentration differences between the cellular functional activity (on-target activity) and cytotoxic activity (approximately three orders of magnitude). Therefore, chemical scaffold-induced, non-specific cellular effects would be avoided when the compound is used at the concentrations ranging from 100 nM to 1 microM. The roughly obtained PK values seem acceptable for in vivo mouse studies; however, whether i.p. administration of UNC0642 modulates the pharmacodynamics of the target (assayed by looking at levels of H3H9me2 in major tissues) would be worthwhile to examine before in vivo applications are pursued.

(last updated: 17 Oct 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The in vitro potency and selectivity against other family members is good. The margin between concentrations that yield a functional effect and cellular toxicity was determined and is at least 80-fold. Limited PK data are provided in the original paper; however, dosing is limited to IP administration, and only Cmax and AUC(0-24hr) are reported. Plasma Cmax at this dose is 1.7 uM. In the absence of protein-binding data at this concentration, relative in vitro potency cannot be estimated, and direct pharmacodynamic data for in vivo target modulation are absent. A second publication (doi:10.1038/nm.4257) reports the in vivo use of this compound using the same dosing regimen, and it shows modulation of maternally repressed gene expression consistent with the in vitro cellular data. Direct demonstration of histone methylation modulation in vivo would increase my confidence in the mechanism of action of this probe.

(last updated: 21 Jan 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

This is a well characterised probe with dual activity against the related targets GLP and G9a. The probe has been evaluated for selectivity against a variety of off-targets including kinases, GPCRs, etc. and appears to be suitably selective. Moreover, selectivity against other related epigenetic targets has also been undertaken and appears satisfactory. Reversibility, cellular activity, etc. are well described and some in vivo data support the use of the probe in model organisms. However, it is worth noting that the probe is recommended for IP dosing only.

(last updated: 18 Jun 2017 )