Jean-Luc Poyet PhD, Molecular Biology & Biochemistry
Course and current status
Dr Poyet completed his doctorate in biochemistry with the study of plants antiviral proteins at the University of Franche-Comté (France) in 1996. After his discovery and analytical study of several adaptor proteins involved in the regulation of the apoptosis and inflammatory responses in Tomas Jefferson University (Philadelphia, USA) as a post doctorate, he joined in 2004 the French National Institute of Health and Medical Research (Inserm) as an Avenir Fellowship recipient. He currently holds a Research Director position at the Inserm. He is also a founding member of CDithem (http://www.cdithem.fr), a consortium that aims at discovering inhibitors or stabilizers of macromolecular interactions with a drug discovery or chemical biology perspective. Jean-Luc Poyet’ team is specialized in the identification of novel therapeutic targets through apoptotic and inflammatory pathways.
Scientific summary
Protein-protein interactions in the control of apoptosis. Therapeutic developments.
Cancer is a major public health issue and a tremendous challenge to drug discovery relative to identifying key therapeutic targets as well as developing breakthrough medicines. The success or failure of a drug discovery program is heavily dependent on the identification and selection of druggable targets. Currently, the lack of novel, validated cancer targets continues to severely limit the emergence of new therapeutics.
Over the past 15 years, evidence has been accumulating that antitumour agents induce apoptosis in cancer cells. Accordingly, evasion of apoptosis, one of the hallmarks of cancer, results in cancer cells resistance to current treatment approaches. Understanding the molecular mechanisms that regulate apoptotic cell death, and how resistant forms of cancer evade apoptotic events, will therefore provide novel opportunities for cancer drug development.
Our work aims to design and develop various drugs that act on key apoptosis regulators to fight cancer. To identify new molecules implicated in the apoptotic signalling pathway, we are combining, in collaboration with Hybrigenics S.A. (Paris) and Les Laboratoires Servier (Neuilly-sur-Seine), a large-scale yeast two-hybrid-based protein-protein interaction mapping with a systematic functional validation in mammalian cells and animal models. Our strategy relies on reiterative screens, starting from proteins with known functions in apoptosis and then repeating the screens using the most significant preys as baits. Biological validation of the identified targets will allow us to establish a complete protein-protein interaction map (‘interactome’) of the apoptosis pathway and identify novel protein-protein interactions as targets for pharmacological intervention. The functional validation of each target includes extensive bibliographic database analysis, monitoring of the endogenous mRNA levels in normal and cancer cells, co-immunoprecipitation and/or co-localization with the bait, in vivo and in vitro protein-protein interaction assays, apoptosis assays following RNA interference (RNAi)-mediated knockdown or expression of dominant negative/positives mutants. Once identified and selected, the targets are used to screen small molecule libraries, via high-throughput chemical or in-silico strategies, in order to identify modulators of the studied protein-protein interactions. These modulators should constitute lead compounds for the development of novel anti-cancer pharmaceuticals.
