Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity

PLoS One. 2017 Aug 14;12(8):e0181601. doi: 10.1371/journal.pone.0181601. eCollection 2017.


Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / analysis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Binding, Competitive / drug effects
  • Biological Availability
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cell Proliferation / drug effects
  • Humans
  • Kinetics
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology
  • Mice, Nude
  • Phenylalanine / metabolism
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Small Molecule Libraries / analysis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Substrate Specificity / drug effects
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Small Molecule Libraries
  • Phenylalanine
  • Protein-Arginine N-Methyltransferases