DS-437

SAM competitive inhibitor of PRMT5, PRMT7

Structure

Information

Protein target names: PRMT5, PRMT7

Mechanism of action: SAM competitive inhibitor

Primary References:

In Vitro Validations

Uniprot ID: O14744
Target Class: Epigenetic
Target SubClass: Protein methyltransferase
Potency: IC50
Potency Value: 5900 nM
Potency Assay: Enzyme inhibition assay-SPA
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Protein arginine N-methyltransferase 5, SKB1, JBP1 ...

DOI Reference: 10.1021/ml500467h

Uniprot ID: O14744
Target Class: Epigenetic
Target SubClass: Protein methyltransferase
Potency: IC50
Potency Value: 25000 nM
Potency Assay: In SPR binding assays with H4 peptide (PRMT5-Mep50)
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Protein arginine N-methyltransferase 5, SKB1, JBP1 ...

DOI Reference: 10.1021/ml500467h

In Cell Validations

In Vivo Data

No in Vivo Validations

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SERP ratings and comments


SERP Ratings

In Cell Rating

(last updated: 18 Aug 2016 )

SERP Ratings

In Cell Rating

SERP 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.

(last updated: 3 Jan 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

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.

(last updated: 5 Jan 2017 )