JQEZ5

SAM competitive inhibitor of EZH2

Structure

Information

Protein target names: EZH2

Mechanism of action: SAM competitive inhibitor

In Vitro Validations

Uniprot ID: Q15910
Target Class: Epigenetic
Target SubClass: Protein methyltransferase
Potency: EZH2
Potency Value: 11 nM
Potency Assay: Radiometric Scintillation Proximity Assay (SPA), Biocore SPR (87 nM)
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Histone-lysine N-methyltransferase EZH2, KMT6, EZH ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

An evaluation of the selectivity of this compound for other targets is missing. Due to the close structural analogy with other known EZH2 inhibitors (UNC1999 and GSK343) that showed no off-target activity with other receptors/enzymes, we could expect the compound to be as well selective for its target. However, I would recommend additional screening to rule out any off-target effects.

(last updated: 3 Aug 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

SAR data are not presented but could presumably have been as other analogs were made. The level of in vitro cellular activity (viability) is relatively low (50% reduction, Fig 6D) given that the compound is dosed 57-fold above the Ki. It would be straightforward to measure cellular uptake and metabolic stability of the compound. The xenograft data are compelling, but off-target effects are worrisome, especially in the absence of in vivo metabolic stability data and additional panel screening (e.g., CEREP).  Little data is presented to show that suppression of EZH2 activity in lung tissue does not have a deleterious effect. It would also help to have broader testing in representative, high-expressing EZH2 NSCLC lines.

(last updated: 11 Sept 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

(last updated: 15 Jun 2017 )