Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation

Protein Arginine Methyltransferases (PRMTs) are crucial players in diverse biological processes, and dysregulation of PRMTs has been linked to various human diseases, especially cancer. Therefore, small molecules targeting PRMTs have profound impact for both academic functional studies and clinical disease treatment. Here, we report the discovery of <i>N</i><sup>1</sup>-(2-((2-chlorophenyl)­thio)­benzyl)-<i>N</i><sup>1</sup>-methylethane-1,2-diamine (<b>28d</b>, DCPR049_12), a highly potent inhibitor of type I PRMTs that has good selectivity against a panel of other methyltransferases. Compound <b>28d</b> effectively inhibits cell proliferation in several leukemia cell lines and reduces the cellular asymmetric arginine dimethylation levels. Serving as an effective inhibitor, <b>28d</b> demonstrates the mechanism of cell killing in both cell cycle arrest and apoptotic effect as well as downregulation of the pivotal mixed lineage leukemia (MLL) fusion target genes such as <i>HOXA9</i> and <i>MEIS1</i>, which reflects the critical roles of type I PRMTs in MLL leukemia. These studies present <b>28d</b> as a valuable inhibitor to investigate the role of type I PRMTs in cancer and other diseases.