title: Identification of small-molecule enhancers of arginine methylation catalyzed by coactivator-associated arginine methyltransferase 1.
abstract: Arginine methylation is a common post-translational modification that is crucial in modulating gene expression at multiple critical levels. The arginine methyltransferases (PRMTs) are envisaged as promising druggable targets, but their role in physiological and pathological pathways is far from being clear due to the limited number of modulators reported to date. In this effort, enzyme activators can be invaluable tools useful as gain-of-function reagents to interrogate the biological roles in cells and in vivo of PRMTs. Yet the identification of such molecules is rarely pursued. Herein we describe a series of aryl ureido acetamido indole carboxylates (dubbed "uracandolates"), able to increase the methylation of histone (H3) or nonhistone (polyadenylate-binding protein 1, PABP1) substrates induced by coactivator-associated arginine methyltransferase 1 (CARM1), both in in vitro and cellular settings. To the best of our knowledge, this is the first report of compounds acting as CARM1 activators.
authors.affiliation: Dipartimento di Scienze Farmaceutiche e Biomediche, Epigenetic Med Chem Lab, Università degli Studi di Salerno, Via Ponte Don Melillo, I-84084 Fisciano (SA), Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.forename: Astrid
authors.initials: A
authors.lastname: Spannhoff
authors.forename: Ciro
authors.initials: C
authors.lastname: Milite
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Dal Piaz
authors.forename: Donghang
authors.initials: D
authors.lastname: Cheng
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tosco
authors.forename: Monica
authors.initials: M
authors.lastname: Viviano
authors.forename: Abdellah
authors.initials: A
authors.lastname: Yamani
authors.forename: Agostino
authors.initials: A
authors.lastname: Cianciulli
authors.forename: Marina
authors.initials: M
authors.lastname: Sala
authors.forename: Vincent
authors.initials: V
authors.lastname: Cura
authors.forename: Jean
authors.initials: J
authors.lastname: Cavarelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.forename: Gianluca
authors.initials: G
authors.lastname: Sbardella
mesh_terms: D001120:Arginine / Q000737:chemistry / Q000235:genetics*; D015153:Blotting, Western; D002384:Catalysis; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000494:pharmacology*; D006657:Histones / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008745:Methylation / Q000187:drug effects*; D015394:Molecular Structure; D039122:Poly(A)-Binding Protein I / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D015534:Trans-Activators
chemical_list: D020536:Enzyme Activators; D006657:Histones; D007211:Indoles; D039122:Poly(A)-Binding Protein I; D054852:Small Molecule Libraries; D015534:Trans-Activators; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1