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

J Med Chem. 2017 Nov 9;60(21):8888-8905. doi: 10.1021/acs.jmedchem.7b01134. Epub 2017 Oct 27.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Arginine / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Diamines / pharmacology
  • Diamines / therapeutic use
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / pathology*
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Repressor Proteins / antagonists & inhibitors

Substances

  • Diamines
  • Enzyme Inhibitors
  • Repressor Proteins
  • Arginine
  • PRMT1 protein, human
  • Protein-Arginine N-Methyltransferases