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Philos Trans R Soc Lond B Biol Sci. 2018 Jun 5;373(1748). pii: 20170072. doi: 10.1098/rstb.2017.0072.

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

Author information

1
CNRS FRE3600 ETaC, bât. IBCG, 31062 Toulouse, France.
2
Maison Française d'Oxford, CNRS, MEAE, 2-10 Norham Road, Oxford, UK.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
4
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
5
Institut National de la Santé et de la Recherche Médicale, U 1258, Illkirch, France.
6
Université de Strasbourg, Illkirch, France.
7
Laboratoire Pierre Fabre, 3 avenue H. Curien, 31100 Toulouse, France.
8
Institute of Biochemistry, Faculty of Chemistry, University Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany.
9
Laboratoire Architecture Fonction des Macromolécules Biologiques (AFMB-UMR 7257), Aix-Marseille Université & CNRS, 163 avenue de Luminy, 13288 Marseille cedex 09, France.
10
Epiremed SAS, 1 Rue des Pénitents Blancs, 31000 Toulouse, France.
11
Laboratoire de chimie moléculaire, CMGPCE, EA7341, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
12
Sorbonne Universités, UPMC Université Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire des Biomolécules (LBM), 4 place Jussieu, 75005 Paris, France.
13
Département de Chimie, Ecole Normale Supérieure, PSL Research University, UPMC Université Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 75005 Paris, France.
14
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France cava@igbmc.fr.
15
CNRS FRE3600 ETaC, bât. IBCG, 31062 Toulouse, France paola.arimondo@etac.cnrs.fr.
16
Churchill College, CB3 0DS Cambridge, UK.

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'.

KEYWORDS:

DNA methylation; PRMT inhibitor; chemical probes; epigenetics; histone methylation; transition state analogues

PMID:
29685976
PMCID:
PMC5915716
DOI:
10.1098/rstb.2017.0072
[Indexed for MEDLINE]
Free PMC Article

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