Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors. (23rd April 2018)

• Record Type: Journal Article
• Authors: Halby, Ludovic; Marechal, Nils; Pechalrieu, Dany; Cura, Vincent; Franchini, Don-Marc; Faux, Céline; Alby, Fréderic; Troffer-Charlier, Nathalie; Kudithipudi, Srikanth; Jeltsch, Albert; Aouadi, Wahiba; Decroly, Etienne; Guillemot, Jean-Claude; Page, Patrick; Ferroud, Clotilde; Bonnefond, Luc; Guianvarc'h, Dominique; Cavarelli, Jean; Arimondo, Paola B.
• Is Part Of: Philosophical transactions. Volume 373:Number 1748(2018)
• Publication Date: 2018-04-23
• Subjects: epigenetics -- DNA methylation -- histone methylation -- transition state analogues -- PRMT inhibitor -- chemical probes; Biology -- Periodicals; Science -- Periodicals; 570
• DOI: 10.1098/rstb.2017.0072
• Languages: English
• ISSNs: 0962-8436

Abstract

Abstract : DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases. Interestingly, compound4 and its derivative2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound4 binds to the PRMT4 active site, displacing strongly the S -adenosyl-l -methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold. This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.