title: Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening.
abstract: Protein arginine methyltransferases (PRMTs) represent an emerging target class in oncology and other disease areas. So far, the most successful strategy to identify PRMT inhibitors has been to screen large to medium-size chemical libraries. Attempts to develop PRMT inhibitors using receptor-based computational methods have met limited success. Here, using virtual screening approaches, we identify 11 CARM1 (PRMT4) inhibitors with ligand efficiencies ranging from 0.28 to 0.84. CARM1 selective hits were further validated by orthogonal methods. Two structure-based rounds of optimization produced 27 (SGC2085), a CARM1 inhibitor with an IC50 of 50 nM and more than hundred-fold selectivity over other PRMTs. These results indicate that virtual screening strategies can be successfully applied to Rossmann-fold protein methyltransferases.
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: David
authors.initials: D
authors.lastname: Smil
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: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Kennedy
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: Structural Genomics Consortium, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Vijayaratnam
authors.initials: V
authors.lastname: Santhakumar
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.|Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7, Canada.
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
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: D053468:CARD Signaling Adaptor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D053468:CARD Signaling Adaptor Proteins; D004791:Enzyme Inhibitors; C426242:CARD11 protein, human; D006162:Guanylate Cyclase