title: A Potent, Selective, and Cell-Active Inhibitor of Human Type I Protein Arginine Methyltransferases.
abstract: Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective, and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical, and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, -3, -4, -6, and -8 but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Eram
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: Yudao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Szewczyk
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Fengling
authors.initials: F
authors.lastname: Li
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: Kyle V
authors.initials: KV
authors.lastname: Butler
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: H Ümit
authors.initials: HÜ
authors.lastname: Kaniskan
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: Brandon A
authors.initials: BA
authors.lastname: Speed
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Carlo
authors.initials: C
authors.lastname: Dela Seña
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Zeng
authors.affiliation: 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.forename: Matthieu
authors.initials: M
authors.lastname: Schapira
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brown
authors.affiliation: 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.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.affiliation: Departments of Structural and Chemical Biology, Oncological Sciences, and Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004983:Ethanolamines; D005029:Ethylenediamines; C000612606:MS023 compound; C000612607:MS094 compound; D011758:Pyrroles; D011484:Protein-Arginine N-Methyltransferases