10.1021/acs.jmedchem.6b01033.s001 Yudao Shen Yudao Shen Magdalena M. Szewczyk Magdalena M. Szewczyk Mohammad S. Eram Mohammad S. Eram David Smil David Smil H. Ümit Kaniskan H. Ümit Kaniskan Renato Ferreira de Freitas Renato Ferreira de Freitas Guillermo Senisterra Guillermo Senisterra Fengling Li Fengling Li Matthieu Schapira Matthieu Schapira Peter J. Brown Peter J. Brown Cheryl H. Arrowsmith Cheryl H. Arrowsmith Dalia Barsyte-Lovejoy Dalia Barsyte-Lovejoy Jing Liu Jing Liu Masoud Vedadi Masoud Vedadi Jian Jin Jian Jin Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6 American Chemical Society 2016 PRMT 4 Protein Arginine Methyltransferase 6 Well-characterized SAR chemical biology studies protein arginine methyltransferases chemical tools PRMT 6 Protein Arginine Methyltransferase 4 049N MS 2016-09-01 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Discovery_of_a_Potent_Selective_and_Cell-Active_Dual_Inhibitor_of_Protein_Arginine_Methyltransferase_4_and_Protein_Arginine_Methyltransferase_6/3830811 Well-characterized selective inhibitors of protein arginine methyltransferases (PRMTs) are invaluable chemical tools for testing biological and therapeutic hypotheses. Based on <b>4</b>, a fragment-like inhibitor of type I PRMTs, we conducted structure–activity relationship (SAR) studies and explored three regions of this scaffold. The studies led to the discovery of a potent, selective, and cell-active dual inhibitor of PRMT4 and PRMT6, <b>17</b> (MS049). As compared to <b>4</b>, <b>17</b> displayed much improved potency for PRMT4 and PRMT6 in both biochemical and cellular assays. It was selective for PRMT4 and PRMT6 over other PRMTs and a broad range of other epigenetic modifiers and nonepigenetic targets. We also developed <b>46</b> (MS049N), which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. Considering possible overlapping substrate specificity of PRMTs, <b>17</b> and <b>46</b> are valuable chemical tools for dissecting specific biological functions and dysregulation of PRMT4 and PRMT6 in health and disease.