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.
