Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1

James Dowden, Richard A Pike, Richard V Parry, Wei Hong, Usama A Muhsen, Stephen G Ward

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Protein arginine N-methyltransferases (PRMTs) selectively replace N-H for N-CH3 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.
Original languageEnglish
Pages (from-to)7814-7821
Number of pages8
JournalOrganic and Biomolecular Chemistry
Volume9
Issue number22
DOIs
Publication statusPublished - 26 Oct 2011

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