title: Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6.
abstract: Well-characterized selective inhibitors of protein arginine methyltransferases (PRMTs) are invaluable chemical tools for testing biological and therapeutic hypotheses. Based on 4, a fragment-like inhibitor of type I PRMTs, we conducted structure-activity relationship (SAR) studies and explored three regions of this scaffold. The studies led to the discovery of a potent, selective, and cell-active dual inhibitor of PRMT4 and PRMT6, 17 (MS049). As compared to 4, 17 displayed much improved potency for PRMT4 and PRMT6 in both biochemical and cellular assays. It was selective for PRMT4 and PRMT6 over other PRMTs and a broad range of other epigenetic modifiers and nonepigenetic targets. We also developed 46 (MS049N), which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. Considering possible overlapping substrate specificity of PRMTs, 17 and 46 are valuable chemical tools for dissecting specific biological functions and dysregulation of PRMT4 and PRMT6 in health and disease.
authors: Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors: Yudao
authors: Y
authors: Shen
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Magdalena M
authors: MM
authors: Szewczyk
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Mohammad S
authors: MS
authors: Eram
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: David
authors: D
authors: Smil
authors: Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors: H Ümit
authors: HÜ
authors: Kaniskan
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Renato Ferreira
authors: RF
authors: de Freitas
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Guillermo
authors: G
authors: Senisterra
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Fengling
authors: F
authors: Li
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
authors: Matthieu
authors: M
authors: Schapira
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Peter J
authors: PJ
authors: Brown
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.|Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
authors: Cheryl H
authors: CH
authors: Arrowsmith
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors: Dalia
authors: D
authors: Barsyte-Lovejoy
authors: Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors: Jing
authors: J
authors: Liu
authors: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
authors: Masoud
authors: M
authors: Vedadi
authors: Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors: Jian
authors: J
authors: Jin
mesh_terms: D001120:Arginine; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D001120:Arginine; C447833:PRMT6 protein, human; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1