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.
Renato Ferreira de Freitas  1 ,  Mohammad S Eram  1 ,  Magdalena M Szewczyk  1 ,  Holger Steuber  2 ,  David Smil  1 ,  Hong Wu  1 ,  Fengling Li  1 ,  Guillermo Senisterra  1 ,  Aiping Dong  1 ,  Peter J Brown  1 ,  Marion Hitchcock  2 ,  Dieter Moosmayer  2 ,  Christian M Stegmann  2 ,  Ursula Egner  2 ,  Cheryl Arrowsmith  1  3 ,  Dalia Barsyte-Lovejoy  1 ,  Masoud Vedadi  1  4 ,  Matthieu Schapira  1  4
Affiliations
  • 1. Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
  • 2. Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
  • 3. Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7, Canada.
  • 4. Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
PMID: 26824386 DOI: 10.1021/acs.jmedchem.5b01772
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.