EI1

Reagent Authentication Certificate:

Chemical Probes Portal EI1.pdf

Protein target name:

EZH2

Mechanism of action:

SAM competitive inhibitor

Recommended Concentration for use in cells:

Up to 1 uM

Probe Availability

MedChem Express (1418308-27-6)

Cayman (1418308-27-6)

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Protein methyltransferase

HUGO ID:

HGNC:3527

Entrez gene ID:

2146

UNIPROT ID:

Q15910

Target alias:

WVS; ENX1; EZH1; KMT6; WVS2; ENX-1; EZH2b; KMT6A, enhancer of zeste 2 polycomb repressive complex 2 subunit

Probe Details

Chemical Probes Portal ID:

CPP631

Probe alias:

KB-145943; 1418308-27-6; GTPL7013; SCHEMBL16197843; 2392AH

PubChem CID:

72199293

ChEMBL ID:

CHEMBL3414574

SMILES string:

CCC(CC)N1C=CC2=C(C=C(C=C21)C#N)C(=O)NCC3=C(C=C(NC3=O)C)C

InChi Key:

PFHDWRIVDDIFRP-UHFFFAOYSA-N

Orthogonal probe:

GSK343CPI-360EPZ-6438

Physico-chemical properties

NMR:

Not available

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

EZH2 13 nM

Potency assay:

In PRC2 enzyme inhibition assays, EI1 had an IC50 = 15 nM against wild-type EZH2 and 13 nM against Y641F EZH2.

Off target activity

Potency assay (off target):

EI1 is 90-fold selective for EZH2 over EZH1 and >10,000-fold selective for the remainder of protein methyltransferases tested (G9a, SUV39H2, SET7/9, CARM1, SMYD2, SETD8, NSD3, SETD2, MLL, and DOTL1).

Probe Selectivity in Vitro:

Not available

In cell validation

On target activity in cells

Potency assay (cells):

In G401, WSU-DLCL2, and GA10 cells, EI1 dose-dependently decreased H3K27 methylation (substrate). In mouse embryonic fibroblasts, EI1 phenocopied genetic depletion of Ezh2.

Target engagement assay (cells):

Indirect, inhibition of protein substrate methylation and genetic depletion experiments

Primary Reference

Reference (doi):

10.1073/pnas.1210371110

Reference (PMID):

23236167

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

El1 is a promising inhibitor with good potency as a SAM competitive inhibitor against EZH2 at 13 nM. El1 was obtained from an initial high-throughput screen to identify the chemotype with the best properties. Optimization of this chemical series resulted in the identification of El1. Although no cell toxicity data were presented, the selectivity profile for El1 against EZH1 (which has >90% homology to EZH2) was greater than 90-fold. El1 also lacks selectivity for wild-type EZH2 over the Y641 EZH2 mutant. No information is presented regarding the pharmacokinetic profile for El1, but the structure seems to comply with the Rule of 5. The molecule should be available through a simple synthetic pathway without additional concerns (like sterocenters). As a functional probe, El1 blocks HMT activity of EZH2 without disrupting the chromatin binding of PRC2, with inhibition of cell proliferation and colony formation.

Sep 12 2016 - 6:54pm

Cell-based activity is oberved at 3.3 uM.

Dec 10 2016 - 11:33pm

EI1

Probe Availability

Probe Information

Target Details

WVS; ENX1; EZH1; KMT6; WVS2; ENX-1; EZH2b; KMT6A, enhancer of zeste 2 polycomb repressive complex 2 subunit

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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EI1

Probe Availability

Probe Information

Target Details

WVS; ENX1; EZH1; KMT6; WVS2; ENX-1; EZH2b; KMT6A, enhancer of zeste 2 polycomb repressive complex 2 subunit

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?