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.

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