title: Discovery of a Potent Class I Protein Arginine Methyltransferase Fragment Inhibitor.
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.
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Renato
authors.initials: R
authors.lastname: Ferreira de Freitas
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Eram
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Magdalena M
authors.initials: MM
authors.lastname: Szewczyk
authors.affiliation: Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Smil
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Hitchcock
authors.affiliation: Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Moosmayer
authors.affiliation: Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Stegmann
authors.affiliation: Pharmaceuticals Division, Bayer Pharma AG, 13353 Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Egner
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.|Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto , Toronto, ON M5S 1A8, Canada.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D012097:Repressor Proteins; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases