The epigenetic mechanisms of regulation have essential roles in carcinogenesis. For example, essential genes for homeostasis as tumour suppressor genes, can be transcriptionally inactivated by aberrant epigenetic changes. These changes are dependent on the activity of several families of enzymes, including histones deacetylases (HDAC) and DNA methyltransferases. These families are both coordinated and interdependent in the gene extinction process. That is why these enzymes may be targets for epigenetic therapies of many cancers. The goal of our work was to inhibit both class of enzyme to obtain antitumour effects responding to the paradigm of re-expression of tumor suppressor genes. We first identified a relatively potent DNA methyltransferase inhibitor on the bacterial DNA methyltransferase model M.HhaI from which we have achieved pharmacomodulations to get compounds with mixed inhibitory activity of DNA methyltransferases and histones deacetylases. These compounds present good anti-cancer activities in vivo. New pharmacomodulations allowed us to get a new series of more active compounds in vitro for inhibition of DNA methyltransferases. From these compounds, we determine a probable mechanism of competition with the cofactor S-Adenosyl-L-Methionine.
|Date of Award||21 Aug 2012|
|Supervisor||Johan Wouters (Supervisor), Didier M. Lambert (Co-Supervisor), Luc WILLEMS (Jury), Jacques Poupaert (Jury), STEVE LANNERS (Jury) & Daniel Vercauteren (President)|