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

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langueAnglais
Pages1465-1481
Nombre de pages17
journalFuture Medicinal Chemistry
Volume9
Numéro13
Les DOIs
étatPublié - 1 sept. 2017

Empreinte digitale

Methyltransferases
DNA
Fluorometry
Mesothelioma
Nucleosides
Epigenomics
Neoplasms
maleimide
RG108
Pharmaceutical Preparations

mots-clés

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    Rondelet, Grégoire ; Fleury, Laurence ; Faux, Céline ; Masson, Véronique ; Dubois, Jean ; Arimondo, Paola B. ; Willems, Luc ; Wouters, Johan. / Inhibition studies of DNA methyltransferases by maleimide derivatives of RG108 as non-nucleoside inhibitors. Dans: Future Medicinal Chemistry. 2017 ; Vol 9, Numéro 13. p. 1465-1481.
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    Inhibition studies of DNA methyltransferases by maleimide derivatives of RG108 as non-nucleoside inhibitors. / Rondelet, Grégoire; Fleury, Laurence; Faux, Céline; Masson, Véronique; Dubois, Jean; Arimondo, Paola B.; Willems, Luc; Wouters, Johan.

    Dans: Future Medicinal Chemistry, Vol 9, Numéro 13, 01.09.2017, p. 1465-1481.

    Résultats de recherche: Contribution à un journal/une revueArticle

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    AU - Rondelet, Grégoire

    AU - Fleury, Laurence

    AU - Faux, Céline

    AU - Masson, Véronique

    AU - Dubois, Jean

    AU - Arimondo, Paola B.

    AU - Willems, Luc

    AU - Wouters, Johan

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