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Hijacking DNA Methyltransferase Transition State Analogues to Produce Chemical Scaffolds for PRMT Inhibitors

Hijacking DNA Methyltransferase Transition State Analogues to Produce Chemical Scaffolds for PRMT Inhibitors

Ludovic Halby, Nils Marechal, Dany Pechalrieu, Vincent Cura, Don-Marc Franchini, Céline Faux, Fréderic Alby, Nathalie Troffer-Charlier, Srikanth Kudithipudi, Albert Jeltsch, Wahiba Aouadi, Etienne Decroly, etc.

Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748):20170072.

PMID: 29685976

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, 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'.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416084	PRMT4 Active human			Price

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