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 I PRMTs catalyze mono- and asymmetric dimethylation of arginine residues and include PRMT1, 3, 4 (also known as CARM1 (Co-activator-associated arginine methyltransferase 1)), 6 and 8. It has been shown that knocking down the expression of PRMT1 or PRMT6 genes (using siRNA) significantly reduces the growth of bladder and lung cancer cells [5]. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses [6,7].
A collaboration between the Icahn School of Medicine at Mount Sinai and the SGC has resulted in MS023 [8], a chemical probe for type I PRMTs, and a structurally similar control compound, MS094. The in vitro and cell-based activity of MS023 is summarized in the table and the Western blots.
(A) MS023 inhibits PRMT1 methyltransferase activity in MCF7 cells. (B) MS094 does not inhibit PRMT1 methyltransferase activity in MCF7 cells. MCF7 cells were treated with MS023 (A) or MS094 (B) at indicated concentrations for 48 h and H4R3me2a levels were determined by Western blot. The graphs represent nonlinear fits of H4R3me2a signal intensities normalized to total histone H4. The results are MEAN ± SEM of two experiments done in triplicate. (C) MS023 inhibits PRMT6 methyltransferase activity in HEK293 cells. HEK293 cells were transfected with FLAG-tagged PRMT6 or its catalytically inactive mutant V86K/D88A (MUT) and treated with MS023 at indicated concentrations for 20 h. H3R2me2a levels were determined by Western blot. The graphs represent nonlinear fits of H3R2me2a signal intensities normalized to total histone H3. The results are MEAN ± SEM of 3 replicates.