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 N1-(2-((2-chlorophenyl)­thio)­benzyl)-N1-methylethane-1,2-diamine (28d, DCPR049_12), a highly potent inhibitor of type I PRMTs that has
good selectivity against a panel of other methyltransferases. Compound 28d effectively inhibits cell proliferation in several leukemia
cell lines and reduces the cellular asymmetric arginine dimethylation
levels. Serving as an effective inhibitor, 28d 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 HOXA9 and MEIS1, which reflects the critical roles of type I PRMTs
in MLL leukemia. These studies present 28d as a valuable
inhibitor to investigate the role of type I PRMTs in cancer and other
diseases.