GSK591 A chemical probe for PRMT5

This probe is available from Cayman Chemical, Tocris and Sigma.

The control may be requested by clicking here.

For any inquiries please contact proberequests@thesgc.org.

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Overview

Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes [1]. Overexpression of PRMTs has been implicated in various human diseases including cancer [2-4]. To date, nine PRMTs have been identified and they are grouped into three categories: types I, II and III. Type II PRMTs, 5 and 9, catalyze symmetric dimethylation of arginine residues, however, PRMT5 is the predominant enzyme for this process. PRMT5 interacts with a number of binding partners that influence its substrate specificity. In particular, MEP50, a member of the WD40 family of proteins, is required for PRMT5 methyltransferase activity.

PRMT5 is reported to have a role in mantle cell lymphoma (MCL) as evidenced by its upregulation in patient samples [5,6]. Consequently, a chemical probe of PRMT5 would be a very useful tool for testing biological and therapeutic hypotheses. The first chemical probe of PRMT5 was co-developed by Epizyme and GlaxoSmithKline (GSK) [7]. An analog of this compound, EPZ015866/GSK3203591 [8], has been kindly donated to the SGC for distribution as GSK591. In an in vitro biochemical assay, GSK591 potently inhibits the PRMT5/MEP50 complex from methylating (histone) H4 with IC50 = 11 nM. In Z-138 cells, GSK591 inhibits the symmetric arginine methylation of SmD3 with EC50 = 56 nM. Further, GSK591 is selective for PRMT5 (up to 50 micromolar) relative to a panel of methyltransferases.

A control compound, SGC2096, that is inactive up to 10 micromolar is also available from the SGC.

In addition, a biotinylated inhibitor, SGC3185 is available

In Vitro potency

Radioactivity assay using H4 (1-15) as substrate

Properties

GSK591

SGC2096

Physical and chemical properties for GSK591
Molecular weight	380.2
Molecular formula	C22H28N4O2
IUPAC name	(3-(3-aza-bicyclo[4.4.0]deca-1(10),6,8-trien-3-yl)-2-hydroxy-propylamino)-(2-cyclobutylamino-pyridin-4-yl)-methanone
MollogP	2.311
PSA	64.84
No. of chiral centres	1
No. of rotatable bonds	8
No. of hydrogen bond acceptors	5
No. of hydrogen bond donors	3

Physical and chemical properties for SGC2096
Molecular weight	332.2
Molecular formula	C18H28N4O2
IUPAC name	(2-cyclobutylamino-pyridin-4-yl)-(2-hydroxy-3-(piperidin-1-yl)-propylamino)-methanone
MollogP	1.991
PSA	65.18
No. of chiral centres	1
No. of rotatable bonds	8
No. of hydrogen bond acceptors	5
No. of hydrogen bond donors	3

SMILES:
GSK591: C1CC(C1)Nc1cc(ccn1)C(NC[C@@H](CN1CCc2ccccc2C1)O)=O
SGC2096: C1CCN(CC1)C[C@H](CNC(c1ccnc(c1)NC1CCC1)=O)O

InChI:
GSK591: InChI=1S/C22H28N4O2/c27-20(15-26-11-9-16-4-1-2-5-18(16)14-26)13-24-22(28)17-8-10-23-21(12-17)25-19-6-3-7-19/h1-2,4-5,8,10,12,19-20,27H,3,6-7,9,11,13-15H2,(H,23,25)(H,24,28)/t20-/m0/s1

SGC2096: InChI=1S/C18H28N4O2/c23-16(13-22-9-2-1-3-10-22)12-20-18(24)14-7-8-19-17(11-14)21-15-5-4-6-15/h7-8,11,15-16,23H,1-6,9-10,12-13H2,(H,19,21)(H,20,24)/t16-/m0/s1

InChIKey:
GSK591: TWKYXZSXXXKKJU-FQEVSTJZSA-N
SGC2096: DCHQEWPVLGTADW-INIZCTEOSA-N

SGC3185

Physical and chemical properties for GSK3185
Molecular weight	854.4
Molecular formula	C42H62N8O9S
IUPAC name	6-(5-(2-(2-(2-(2-(3-(3-(4-((3-(3-aza-bicyclo[4.4.0]deca-1(10),6,8-trien-3-yl)-2-hydroxy-propylamino)-formyl)-pyridin-2-ylamino)-azetidin-1-yl)-3-oxo-propoxy)-ethoxy)-ethoxy)-ethoxy)-ethylamino)-5-oxo-pentyl)-7-thia-2,4-diaza-bicyclo[3.3.0]octan-3-one
MollogP	1.341
PSA	175.1
No. of chiral centres	4
No. of rotatable bonds	30
No. of hydrogen bond acceptors	16
No. of hydrogen bond donors	6

SMILES: [H][C@@]12[C@H](CCCCC(NCCOCCOCCOCCOCCC(N3CC(C3)Nc3cc(ccn3)C(NC[C@@H](CN3CCc4ccccc4C3)O)=O)=O)=O)SC[C@]1([H])NC(N2)=O

InChI: InChI=1S/C42H62N8O9S/c51-34(28-49-14-10-30-5-1-2-6-32(30)25-49)24-45-41(54)31-9-12-43-37(23-31)46-33-26-50(27-33)39(53)11-15-56-17-19-58-21-22-59-20-18-57-16-13-44-38(52)8-4-3-7-36-40-35(29-60-36)47-42(55)48-40/h1-2,5-6,9,12,23,33-36,40,51H,3-4,7-8,10-11,13-22,24-29H2,(H,43,46)(H,44,52)(H,45,54)(H2,47,48,55)/t34-,35-,36-,40-/m0/s1

InChIKey: PZIWNLNYZRZJCY-VNLYVSNMSA-N

Selectivity Profile