title: Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1.
abstract: Protein arginine N-methyltransferases (PRMTs) selectively replace N-H for N-CH(3) at substrate protein guanidines, a post-translational modification important for a range of biological processes, such as epigenetic regulation, signal transduction and cancer progression. Selective chemical probes are required to establish the dynamic function of individual PRMTs. Herein, model inhibitors designed to occupy PRMT binding sites for an arginine substrate and S-adenosylmethionine (AdoMet) co-factor are described. Expedient access to such compounds by modular synthesis is detailed. Remarkably, biological evaluation revealed some compounds to be potent inhibitors of PRMT1, but inactive against CARM1. Docking studies show how prototype compounds may occupy the binding sites for a co-factor and arginine substrate. Overlay of PRMT1 and CARM1 binding sites suggest a difference in a single amino acid that may be responsible for the observed selectivity.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham, UK NG7 2RD. james.dowden@nottingham.ac.uk
authors.forename: James
authors.initials: J
authors.lastname: Dowden
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pike
authors.forename: Richard V
authors.initials: RV
authors.lastname: Parry
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
authors.forename: Usama A
authors.initials: UA
authors.lastname: Muhsen
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Ward
mesh_terms: D001120:Arginine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D044127:Epigenesis, Genetic; D004926:Escherichia coli; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008970:Molecular Weight; D010957:Plasmids; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013379:Substrate Specificity; D014169:Transformation, Bacterial
chemical_list: D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D012436:S-Adenosylmethionine; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1