Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor

J Med Chem. 2016 Feb 11;59(3):1176-83. doi: 10.1021/acs.jmedchem.5b01772. Epub 2016 Jan 29.

Abstract

Protein methyltransferases (PMTs) are a promising target class in oncology and other disease areas. They are composed of SET domain methyltransferases and structurally unrelated Rossman-fold enzymes that include protein arginine methyltransferases (PRMTs). In the absence of a well-defined medicinal chemistry tool-kit focused on PMTs, most current inhibitors were identified by screening large and diverse libraries of leadlike molecules. So far, no successful fragment-based approach was reported against this target class. Here, by deconstructing potent PRMT inhibitors, we find that chemical moieties occupying the substrate arginine-binding site can act as efficient fragment inhibitors. Screening a fragment library against PRMT6 produced numerous hits, including a 300 nM inhibitor (ligand efficiency of 0.56) that decreased global histone 3 arginine 2 methylation in cells, and can serve as a warhead for the development of PRMT chemical probes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Protein-Arginine N-Methyltransferases / metabolism
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Structure-Activity Relationship

Substances

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