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Les Benzo[e]pyridoindoles, une nouvelle famille d'inhibiteurs de kinase à activité anti-proliférative

Abstract : Benzo[e]pyridoindole is identified as the novel Aurora inhibiteurs. The most potent compound, C1, inhibits efficiently both Aurora B and CHK2. Thus, we exploited the potency of this molecule in combined treatment applications based on its sharp and multiple specificities. We set up the combined treatments (Etoposide plus C1) on different cell lines and obtained an additive effect on H358 and a synergic one for HL60 and U2OS cells. This combination prevents the spheroid development as well as the cellular xenograft expansion. One of the main advantages of this combination is to decrease the dose of DNA damage agents in therapy leading to the reduction of their toxicity. C1 inhibiting both CHK2 and Aurora B open the way to targeted pharmacology based on simultaneous alteration of mitotic onset and DNA damage defences. Benzo[e]pyridoindole family has a penta-heterocyclic form with 3 lateral chains. The variations of these lateral chains can affect the inhibitory activity of the compounds. We researched the antimitotic efficiency of several benzo[e]pyridoindoles. This structure/function study drives to define the contribution of lateral chains in inhibitory activity and will direct future synthesis. We focused on compound C4 that induced an unusual profile of Histone H3 phosphorylation since it prevents it only in early mitosis. We found that H3-phosphorylation is not essential for chromosome organisation. Finally, we characterized the molecule C21 that is a potent antiproliferative compound both in cellulo and in vivo. This work reveals the potency of benzo[e]pyridoindoles as antiproliferative compounds.
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Submitted on : Thursday, October 4, 2012 - 1:02:02 AM
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Lien Vu Hong. Les Benzo[e]pyridoindoles, une nouvelle famille d'inhibiteurs de kinase à activité anti-proliférative. Biologie cellulaire. Université de Grenoble, 2011. Français. ⟨NNT : 2011GRENV049⟩. ⟨tel-00738295⟩

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