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Synthèse de nouveaux inhibiteurs de kinases Pim et de modulateurs des protéines de la famille des Bcl-2, anticancéreux potentiels

Abstract : Cancer development is associated with dysfunctions in cell cycle progression or apoptosis. The identification of cellular agents involved in this disease, and the elucidation of mechanisms responsible for these dysfunctions provide the basis for the development of novel anti-cancer drugs.Thus, Pim kinases and Bcl-2 anti-apoptotic proteins which are overexpressed in many malignancies and contribute significantly to chemoresistance are of great interest for the development of targeted cancer therapy. Pim kinases (Pim-1,-2 and -3) belong to a family of serine / threonine kinases which play a key role in cell survival, proliferation and differenciation. Although all protein kinases share ATP as a common substrate, the structure of the ATP-binding pocket of Pim kinases is unique and offers an opportunity for a selective inhibition. Taking account of these specificities, we were interested in the synthesis of novel selective ATP competitive Pim kinase inhibitors. Among the other agents involved in tumorigenesis, Bcl-2 family proteins, which govern apoptosis (or programmed cell death), are subject of a recent interest. These proteins are divided in two classes depending on their function : pro-apoptotic and anti-apoptotic members that are overexpressed in a variety of cancers. In a preliminary work in the laboratory, alkoxyquinoline trimers have demonstrated micromolar inhibition against antiapoptotic proteins Bcl-2 and Bcl-xL. Therefore, we carried on this structure-activity relationship study with the synthesis of novel analogues.
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Emmanuelle Saugues. Synthèse de nouveaux inhibiteurs de kinases Pim et de modulateurs des protéines de la famille des Bcl-2, anticancéreux potentiels. Autre. Université Blaise Pascal - Clermont-Ferrand II, 2011. Français. ⟨NNT : 2011CLF22170⟩. ⟨tel-00743912⟩

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