EPZ020411

Reagent Authentication Certificate:

Chemical Probes Portal EPZ004777.pdf

Protein target name:

PRMT6

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

40 nM - 1 uM

Probe Availability

MedChem Express (1700663-41-7)

Cayman (1700663-41-7)

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Protein methyltransferase

HUGO ID:

HGNC:18241

Entrez gene ID:

55170

UNIPROT ID:

Q96LA8

Target alias:

HRMT1L6

Probe Details

Chemical Probes Portal ID:

CPP62

Probe alias:

CS-5006, HY-12970, 49L

PubChem CID:

91668547

ChEMBL ID:

CHEMBL3589039

SMILES string:

CNCCN(C)CC1=CNN=C1C2=CC=C(O[C@H]3C[C@H](OCCC4CCOCC4)C3)C=C2

InChi Key:

QMDKVNSQXPVCRD-UHFFFAOYSA-N

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H-NMR (300 MHz, D2O): δ 7.89(s, 1H), 7.43(d, J=4.5Hz, 2H), 6.98(d, J=4.4Hz, 2H), 4.94-4.87(m, 1H), 4.42(s, 2H),

4.31-4.23(m, 1H), 3.90-3.85(m, 2H), 3.47-3.34(m, 4H), 3.20(s, 4H), 2.61(s, 3H), 2.56(s, 3H), 2.48-2.37(m, 4H), 1.65-1.57(m, 3H), 1.50-1.44(m, 2H), 1.29-1.14(m, 2H) ppm.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

0.010 uM

Potency assay:

Inhibition of 3H-SAM-dependent labeling of peptide substrate and quantification of 3H-labeled peptide.

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

4Y30

Structure-activity relationship:

Yes, 21 compounds with in vitro IC50 data for PRMT6, PRMT8, and PRMT. Analogues with selectivity for PRMT6 over both PRMT1 and PRMT8 were obtained by extending further off the para position of the aryl group. Increased potency for PRMT6 compared to PRMT1 and PRMT8 was achieved with oxygen- and nitrogen-linked alkyl compounds.

Off target activity

Potency (off target):

IC50

Off target protein and potency:

PRMT8 0.223 uMPRMT1 0.119 uM

Potency assay (off target):

Same as on-target assay. The probe was also >100-fold selective against other methyltransferases, including PRMT3, PRMT4, PRMT5, and PRMT7.

Probe Selectivity in Vitro:

Unknown

In cell validation

On target activity in cells

Potency in cells:

IC50

0.0637 uM

Potency assay (cells):

H3R2 methylation in PRMT6-overexpressing A375 cells.

Target engagement assay (cells):

Yes, indirect. Substrate methylation assay as noted above.

Off target activity in cells

Potency assay, off target (cells):

The probe was 10-fold selective for PRMT6 > PRMT1 by comparing methylation of PRMT6-specific substrates to PRMT1 substrates in A375 cells.

Probe Selectivity in Cell:

Unknown

In vivo validation

Organism:

male Sprague-Dawley rats

Dose:

5 mg/mL

Route of delivery:

Subcutaneous

Plasma half life:

9.19 h

Fraction of probe bound to plasma protein:

0.48

Cmax:

844 ng/mL

Tmax:

0.444 h

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.5b00071

Reference (PMID):

26101569

Endorsed probe

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

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

Selectivity over some other isoforms of arginine methyltransferase is limited 10 - 20 fold. No data is available on CNS exposure of EPZ02041.

Jun 12 2016 - 4:05am

EPZ020411 is not greatly selective for PRMT6 over PRMT1 or PRMT8 in vitro. PRMT6 is the only PRMT known to methylate the H3R2 position, and EPZ020411 can be used as a probe to assess the functionality of this post-translational modification. While this compound shows poor bioavailability following oral dosing (<5%), subcutaneous (SC) dosing results in significant plasma levels, making this compound suitable for in vivo studies of the H3R2 mark using SC dosing.

Jun 19 2016 - 6:58pm

EPZ020411 is a potent inhibitor of PRMT6 in biochemical (IC50 = 10 nM) and cellular (IC50 = 600 nM) assays EPZ020411 is selective against the related enzymes PRMT3, PRMT4, PRMT5, and PRMT7 in a biochemical assay, and relatively selective against PRMT1 and PRMT8, in biochemical (IC50's = 100 and 200 nM, respectively) and cellular assays (for PRMT1). Even though EPZ020411 is selective within the PRMT family, there is no information on other relevant human methyltransferases. (See 10.1021/acs.jmedchem.5b01772 and 10.1021/acschembio.5b00839 for examples of PRMT6 inhibitors profiled vs. other methyltransferases). In vivo EPZ020411 is 65% bioavailable following 5 mg/kg s.c. administration. Unfortunately, the unbound blood concentration of EPZ020411 is above the H3R2-methylation IC50 (cellular assay) for less than 6h. Additional studies will be required to define if this exposure is enough for a relevant pharmacological effect in vivo.

Mar 12 2020 - 12:00pm

EPZ020411

Probe Availability

Probe Information

Target Details

HRMT1L6

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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EPZ020411

Probe Availability

Probe Information

Target Details

HRMT1L6

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?