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Rational Design and Synthesis of Selective PRMT4 Inhibitors: A New Chemotype for Development of Cancer Therapeutics** |
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| Authors: | Dr Mathew Sutherland Alice Li Anissa Kaghad Dimitrios Panagopoulos Dr Fengling Li Dr Magdalena Szewczyk Dr David Smil Dr Cora Scholten Dr Léa Bouché Dr Timo Stellfeld Dr Cheryl H Arrowsmith Dr Dalia Barsyte Dr Masoud Vedadi Dr Ingo V Hartung Dr Holger Steuber Dr Robert Britton Dr Vijayaratnam Santhakumar |
| Affiliation: | 1. Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6 Canada;2. Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7 Canada;3. Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7 Canada
Ontario Institute for Cancer Research, 661 University Ave, Toronto, ON M5G 0A3 Canada;4. Bayer A.G. Research and Development, Pharmaceuticals Muellerstr. 178, 13442 Berlin, Germany;5. Bayer A.G. Research and Development, Pharmaceuticals Muellerstr. 178, 13442 Berlin, Germany Innovation Campus Berlin, Nuvisan ICB GmbH, Müllerstraße 178, 13353 Berlin, Germany;6. Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7 Canada Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, 610 University Ave, Toronto, ON M5G 2C1 Canada;7. Structural Genomics Consortium, University of Toronto, MaRS Centre, South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7 Canada Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Cir, Toronto, ON M5S 1A8 Canada;8. Bayer A.G. Research and Development, Pharmaceuticals Muellerstr. 178, 13442 Berlin, Germany Merck Healthcare KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany |
| Abstract: | Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates the arginine residues of histone H3 and nonhistone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and, potentially, therapeutics. Although several PRMT4 inhibitors have been reported, most display poor selectivity against other members of the PRMT family of methyl transferases. Herein, we report the structure-based design of a new class of alanine-containing 3-arylindoles as potent and selective PRMT4 inhibitors, and describe key structure–activity relationships for this class of compounds. |
| Keywords: | co-crystal structures methylation protein arginine methyl transferases structure-based drug design |