Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors.

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

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, compound 4 and its derivative 2 showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound 4 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'.