Diamidine compounds for selective inhibition of protein arginine methyltransferase 1

J Med Chem. 2014 Mar 27;57(6):2611-22. doi: 10.1021/jm401884z. Epub 2014 Mar 6.


Protein arginine methylation is a posttranslational modification critical for a variety of biological processes. Misregulation of protein arginine methyltransferases (PRMTs) has been linked to many pathological conditions. Most current PRMT inhibitors display limited specificity and selectivity, indiscriminately targeting many methyltransferase enzymes that use S-adenosyl-l-methionine as a cofactor. Here we report diamidine compounds for specific inhibition of PRMT1, the primary type I enzyme. Docking, molecular dynamics, and MM/PBSA analysis together with biochemical assays were conducted to understand the binding modes of these inhibitors and the molecular basis of selective inhibition for PRMT1. Our data suggest that 2,5-bis(4-amidinophenyl)furan (1, furamidine, DB75), one leading inhibitor, targets the enzyme active site and is primarily competitive with the substrate and noncompetitive toward the cofactor. Furthermore, cellular studies revealed that 1 is cell membrane permeable and effectively inhibits intracellular PRMT1 activity and blocks cell proliferation in leukemia cell lines with different genetic lesions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding, Competitive / drug effects
  • Catalytic Domain / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Fluorescence Polarization
  • Humans
  • Immunoprecipitation
  • Kinetics
  • Leukemia / drug therapy
  • Leukemia / metabolism
  • Models, Molecular
  • Pentamidine / analogs & derivatives*
  • Pentamidine / chemical synthesis
  • Pentamidine / pharmacology*
  • Protein Binding
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Repressor Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship


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