Protein substrate competitive inhibitor, SAM uncompetitive inhibitor of PRMT5



Protein target names: PRMT5

Mechanism of action: Protein substrate competitive inhibitor, SAM uncompetitive inhibitor

Recommended in-cell concentration:
300 nM - 2.5 uM

In Vitro Validations

Uniprot ID: O14744
Target Class: Epigenetic
Target SubClass: Protein methyltransferase
Potency: Ki
Potency Value: 5 nM
Potency Assay: Homogeneous time-resolved fluorescence (HTRF) assay under balanced conditions to monitor the monomethylation of H4R3 on a histone H4 peptide by PRMT5:MEP50
PDB ID for probe-target interaction (3D structure): 4GQB 4X60 4X63
Structure-activity relationship: Yes
Target aliases:
Protein arginine N-methyltransferase 5, SKB1, JBP1 ...

DOI Reference: 10.1021/acsmedchemlett.5b00380

In Cell Validations

In Vivo Data

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SERP ratings and comments

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

There is clear evidence showing EPZ015666 inhibits PRMT5 directly in cell-free experiments, including several orthogonal biochemical assays, X-ray crystallography, surface plasmon resonance, SAR, appropriate counter-screens for assay artifacts and binding kinetics. There is also solid evidence showing target engagement in cells, notably through the use of CETSA and a functional readout (i.e., reduction in SmD3me2s signal). Available evidence suggests this is an sound chemical probe with oral bioavailability and demonstrated efficacy in mouse xenograft models, both with reduction in tumor volume (Z-138 and Maver-1 cells) and PRMT5 target inhibition (SDMA levels). Additional evidence that would strengthen confidence in the use of EPZ015666 includes additional selectivity data (e.g., other epigenetic enzyme classes and unrelated classes as well), cytotoxicity data versus other standard cell lines, additional PK data (e.g., under conditions where the dosage and formulation more closely approximates the xenograft studies), and demonstration of in vivo target engagement (e.g., CETSA). This probe should be used in conjunction with its inactive analog, EPZ019896, to control for off-target effects.

(last updated: 27 May 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

EPZ015666 is an excellent potent and selective PRMT5 probe that can be used in cellular systems.

(last updated: 30 May 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

SERP Comments:

The reported data for this compound shows potent biochemical and cellular inhibition of the target, and preliminary single dose pharmokinetic (PK) data suggests good coverage above IC90 for 12 hr @ 100 mg/kg. Physicochemical properties are acceptable. Note that no selectivity data against related family targets are reported and, as such, there remains a possibility that off-target pharmacology may be observed. However, on-target pharmacology is demonstrated with reduction of downstream products.

(last updated: 21 Jun 2016 )