Benzo[e]pryridoindolones, nouveaux inhibiteurs de kinases hydrosolubles à fort potentiel anti-prolifératif - Institut Albert Bonniot Accéder directement au contenu
Thèse Année : 2013

Benzo[e]pryridoindolones,new hydrosoluble kinase inhibitors with high anti-proliferative activity

Benzo[e]pryridoindolones, nouveaux inhibiteurs de kinases hydrosolubles à fort potentiel anti-prolifératif

Résumé

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.
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.
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Dates et versions

tel-01066000 , version 1 (19-09-2014)

Identifiants

  • HAL Id : tel-01066000 , version 1

Citer

Ly Thuy Tram Le. Benzo[e]pryridoindolones, nouveaux inhibiteurs de kinases hydrosolubles à fort potentiel anti-prolifératif. Sciences agricoles. Université de Grenoble, 2013. Français. ⟨NNT : 2013GRENV019⟩. ⟨tel-01066000⟩
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