Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5449-53. doi: 10.1016/j.bmcl.2015.06.095. Epub 2015 Jul 3.

Abstract

Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 μM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 μM, 13.1 μM and 11.4 μM, respectively.

Keywords: Epigenetics; PRMT1; Protein arginine methyltransferase; Small molecule inhibitor; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology
  • Animals
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology*
  • Binding Sites
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Discovery*
  • Enzyme Activation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Models, Biological*
  • Molecular Structure
  • Nitro Compounds / chemistry
  • Nitro Compounds / pharmacology
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Amides
  • Benzimidazoles
  • Nitro Compounds
  • Pyrimidines
  • Protein-Arginine N-Methyltransferases