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

[en] 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.

Research Center/Unit :

CNRS

Disciplines :

Oncology
Oncology

Author, co-author :

Rondelet, Grégoire; U Namur > Department of Chemistry

Fleury, Laurence

Faux, Céline

Masson, Véronique

Dubois, Jean

Arimondo, Paola

Willems, Luc ; Université de Liège - ULiège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Microbial, food and biobased technologies

Wouters, Johan

Language :

English

Title :

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

Publication date :

10 August 2017

Journal title :

Future Medicinal Chemistry

ISSN :

1756-8919

eISSN :

1756-8927

Publisher :

Future Science, United Kingdom

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
the Fondation InNaBioSanté
the National Research Agency
Investissement d’avenir

Available on ORBi :

since 31 January 2018

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