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

Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor.

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Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7, Canada.
Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.


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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