Thèse de doctorat en Biologie cellulaire
Sous la direction de Annie Molla.
Soutenue le 18-09-2013
à Grenoble , dans le cadre de École doctorale chimie et science du vivant (Grenoble) , en partenariat avec CRI IAB - Centre de Recherche Oncologie/Développement - Institut Albert Bonniot de Grenoble (laboratoire) , Equipe 4 - Dimitrov (équipe de recherche) et de Epidémiologie pronostique des cancers et affections graves (laboratoire) .
Nous étudions une nouvelles familles d'inhibiteurs de kinase: les benzopyridoindole. Ces molécules ont des effets antiprolifératifs sur des lignées cancéreuses et représentent les têtes de série de possibles agents anti-cancéreux. We study on a new family of kinase inhibitors: benzopyridoindole. These molecules have antiproliferative effects on cancer cell lines and represent the lead of potential anti-cancer products.
Benzo[e]pryridoindolones,new hydrosoluble kinase inhibitors with high anti-proliferative activity
Benzo[e]pyridoindoles are novel potent inhibitors of aurora kinases. We performed a SAR study to improve their activity and water solubility. Amino-benzo[e]pyridoindolones were found to be potent hydrosoluble anti-proliferative molecules. They induced a massive arrest in mitosis, prevented histone H3 phosphorylation as well as disorganizing the mitotic spindles. Upon a delay, cells underwent binucleated and finally died. Taking into account their interesting preclinal characteristics, their efficiency towards xenografts in nude mice and their apparent safety in animals, these molecules are promising new anti-cancer drugs. They probably target a metabolic signaling pathway, besides aurora B inhibition. In addition to their possible applications, these inhibitors are tools for cell biology studies. C4, a low ATP affinity inhibitor of aurora B kinase, revealed that the basal activity of the kinase is required for histone H3 phosphorylation in prophase and for chromosome compaction in anaphase. These waves of activation/deactivation of the kinase, during mitosis, corresponded to different conformations of the passenger chromosomal complex.