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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 language | English |
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Pages (from-to) | 7814-7821 |
Number of pages | 8 |
Journal | Organic and Biomolecular Chemistry |
Volume | 9 |
Issue number | 22 |
DOIs | |
Publication status | Published - 26 Oct 2011 |
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Dive into the research topics of 'Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1'. Together they form a unique fingerprint.Projects
- 1 Finished
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THE ROLE OF PROTEIN ARGININE METHYLATION IN T LYMPHOCYTE MIG RATION
Ward, S. (PI)
1/03/08 → 28/02/10
Project: Research council