DS-437

Protein target name:

PRMT5, PRMT7

Mechanism of action:

SAM competitive inhibitor

Recommended Concentration for use in cells:

N/A

Probe Availability

MilliporeSigma (1674364-87-4)

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Protein methyltransferase

HUGO ID:

HGNC:10894 HGNC:25557

Entrez gene ID:

10419 54496

UNIPROT ID:

O14744 Q9NVM4

Target alias:

JBP1; SKB1; IBP72; SKB1Hs; HRMT1L5, protein arginine methyltransferase 5, protein arginine methyltransferase 7

Probe Details

Chemical Probes Portal ID:

CPP638

Probe alias:

GTPL8395; DS437; DS-437

PubChem CID:

91827358

ChEMBL ID:

CHEMBL3577854

SMILES string:

CCNC(=O)NCCSC[C@H]1O[C@H]([C@H](O)[C@@H]1O)n2cnc3c(N)ncnc23

InChi Key:

CACMCLIHCDTJHL-IDTAVKCVSA-N

Orthogonal probe:

GSK591EPZ015666

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

6 uM

Potency assay:

Enzyme inhibition assay-SPA; In SPR binding assays with H4 peptide (PRMT5-Mep50), IC50=25 uM and with H2B peptide (PRMT7), IC50=37 uM.

Off target activity

Potency assay (off target):

DS-437 was inactive against a panel of 27 protein, RNA and DNA methyltransferases with residual activity against DNMT3A and DNMT3B (IC50 > 50 uM).

Probe Selectivity in Vitro:

Not available

In cell validation

On target activity in cells

Potency in cells:

IC50

PRMT5 1 uM, PRMT7 8 uM

Potency assay (cells):

In MB-MDA231 cells, DS-437 inhibited protein substrate methylation (SmD and SmB proteins).

Target engagement assay (cells):

Indirect, inhibition of protein substrate methylation

Primary Reference

Reference (doi):

10.1021/ml500467h

Reference (PMID):

25893041

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This compound has not been used in animals. DS-437 exhibits an IC50 of 6 uM in vitro and is a dual inhibitor of PRMT5 and PRMT7. In the original publication, this compound is proposed as a chemical scaffold for the development of potent and cell-active chemical probes to investigate the PRMT5-PRMT7 arginine methylation pathways.

Jan 4 2017 - 11:32am

DS-437 is the only dual inhibitor for PRMT5 and PRMT7, and currently the only (documented) SAM-competitive inhibitor of PRMT5. Given the growing importance of both methyltransferases, especially with respect to the symmetric dimethyl arginine mark, DS-437 may add value when used in parallel with other chemical probes in an explorative phenotypic assay. Workman and Collins (http://dx.doi.org/10.1016/j.chembiol.2010.05.013) recommend chemical probes have cellular potency <1-10 μM, while also demonstrating dose-dependent inhibition. DS-437 meets these requirements for PRMT5 (~1 μM) but not for PRMT7 (~18 μM) in a biomarker assay using the SmD3 peptide AGRGRGKAAILKAQVAARGRGRGMGRGN as the substrate. IC50 values of ~ 1 μM and ~18 μM (Hill slope: 1.0 in both cases) were determined for PRMT5-‐MEP50 and PRMT7, respectively. Selectivity against PRMT4 and PRMT9 and broader off-target profiling (as with Cerep and/or the Psychoactive Drug Screening Program (PDSP)) are not provided but would be helpful to fully interpret results.

Jan 9 2017 - 3:04pm

DS-437

Probe Availability

Probe Information

Target Details

JBP1; SKB1; IBP72; SKB1Hs; HRMT1L5, protein arginine methyltransferase 5, protein arginine methyltransferase 7

Probe Details

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

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DS-437

Probe Availability

Probe Information

Target Details

JBP1; SKB1; IBP72; SKB1Hs; HRMT1L5, protein arginine methyltransferase 5, protein arginine methyltransferase 7

Probe Details

In vitro validation

In cell validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?