Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

J Med Chem. 2017 Jul 27;60(14):6289-6304. doi: 10.1021/acs.jmedchem.7b00587. Epub 2017 Jul 12.


PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 μM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemical synthesis
  • Acetanilides / chemistry*
  • Acetanilides / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Databases, Chemical
  • Drug Screening Assays, Antitumor
  • Humans
  • Kinetics
  • Leukemia
  • Lymphoma
  • Methylation
  • Models, Molecular
  • Molecular Docking Simulation
  • Protein Binding
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / chemistry
  • Protein-Arginine N-Methyltransferases / metabolism
  • Structure-Activity Relationship
  • snRNP Core Proteins / metabolism


  • Acetanilides
  • Antineoplastic Agents
  • Benzimidazoles
  • SNRPD3 protein, human
  • methyl 2-(2-((5-methoxy-1H-benzo(d)imidazol-2-yl)thio)acetamido)benzoate
  • snRNP Core Proteins
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases