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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain*
  • Humans
  • Methyltransferases / chemical synthesis*
  • Peptides / metabolism*


  • Peptides
  • Methyltransferases

Associated data

  • figshare/10.6084/m9.figshare.c.4025908