GSK591

Reagent Authentication Certificate:

Chemical Probes Portal GSK591.pdf

Protein target name:

PRMT5

Mechanism of action:

protein substrate competitive inhibitorSAM uncompetitive inhibitor

Recommended Concentration for use in cells:

10 nM - 1 uM

Probe Availability

Tocris (1616391-87-7)

MedChem Express (1616391-87-7)

MilliporeSigma (1616391-87-7)

Cayman (1616391-87-7)

Probe Information

Target and Probe Information

Target Details

Target class:

Epigenetics

Subclass:

Protein methyltransferase

HUGO ID:

HGNC:10894

Entrez gene ID:

10419

UNIPROT ID:

O14744

Target alias:

JBP1, SKB1, IBP72, SKB1Hs, HRMT1L5

Probe Details

Chemical Probes Portal ID:

CPP153

Probe alias:

GTPL8954, EPZ015866, GSK3203591

PubChem CID:

117072552

SMILES string:

C1CC(C1)NC2=NC=CC(=C2)C(=O)NC[C@@H](CN3CCC4=CC=CC=C4C3)O

InChi Key:

TWKYXZSXXXKKJU-FQEVSTJZSA-N

Orthogonal probe:

EPZ015666DS-437

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H-NMR (400MHz, MeOD-d4) δ ppm: 7.90 d, 1H, J=8.0Hz), 7.12 (m, 3H), 7.05 (m, 1H), 6.80 (s, 1H), 6.75 (d, 1H, J=5.2Hz), 4.24 (m, 1H), 4.12 (m ,1H), 3.75 (s, 2H), 3.54 (dd, 1H, J=8.0, 5.2Hz), 3.47 (dd, 1H, J=6.8, 6.4Hz), 2.93-2.88 (m, 4H), 2.67 (m, 2H), 2.43 (m, 2H), 1.92 (m, 2H), 1.81 (m, 2H)

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

4 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.

Structure-activity relationship:

Yes. Early SAR exploration around the THIQ motif confirmed the contribution of the cation−π interaction with cofactor SAM and was thus retained within the series as a key binding interaction.

Off target activity

Potency assay (off target):

No inhibition of 20 Protein methyltransferases at 50 uM (PRMT8, PRMT1, PRMT3, PRMT6, PRMT7, CARM1, DOT1L, SMYD2, SMYD3, SETD7, EZH1, EZH2, SUV39H1, EHMT1, EHMT2, SETDB1, SETD2, NSD1, WHSC1L1, WHSC1)

Probe Selectivity in Vitro:

Unknown

In cell validation

On target activity in cells

Potency in cells:

IC50

3 nM

Potency assay (cells):

In-cell western assay following inhibition of symmetric dimethylation of arginine-containing substrates in Z-138 cells over 4 days.

Primary Reference

Reference (doi):

10.1021/acsmedchemlett.5b00380

Reference (PMID):

26985292

External Resources

Available data:

GDSC2

GSK591

Probe Availability

Probe Information

Target Details

JBP1, SKB1, IBP72, SKB1Hs, HRMT1L5

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

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GSK591

Probe Availability

Probe Information

Target Details

JBP1, SKB1, IBP72, SKB1Hs, HRMT1L5

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?