Inhibition studies of DNA methyltransferases by maleimide derivatives of RG108 as non-nucleoside inhibitors

Grégoire Rondelet, Laurence Fleury, Céline Faux, Véronique Masson, Jean Dubois, Paola B. Arimondo, Luc Willems, Johan Wouters

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Aim: DNA methyltransferases (DNMTs) are important drug targets for epigenetic therapy of cancer. Nowadays, non-nucleoside DNMT inhibitors are in development to address high toxicity of nucleoside analogs. However, these compounds still have low activity in cancer cells and mode of action of these compounds remains unclear. Materials & methods: In this work, we studied maleimide derivatives of RG108 by biochemical, structural and computational approaches to highlight their inhibition mechanism on DNMTs. Results: Findings demonstrated a correlation between cytotoxicity on mesothelioma cells of these compounds and their inhibitory potency against DNMTs. Noncovalent and covalent docking studies, supported by crystallographic (apo structure of M.HhaI) and differential scanning fluorimetry assays, provided detailed insights into their mode of action and revealed essential residues for the stabilization of such compounds inside DNMTs. </inline-graphic.

Original languageEnglish
Pages (from-to)1465-1481
Number of pages17
JournalFuture Medicinal Chemistry
Issue number13
Publication statusPublished - 1 Sep 2017



  • apoenzyme crystal structure
  • DNA methylation
  • DNA methyltransferases
  • epigenetics
  • Michael acceptor

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