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Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode

Abstract : Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-x L and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-x L pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyr-idoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-x L targeting strategies.
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Submitted on : Monday, January 14, 2019 - 4:08:16 PM
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Siham Hedir, Marcella de Giorgi, Jade Fogha, Martina de Pascale, Louis-Bastien Weiswald, et al.. Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode. European Journal of Medicinal Chemistry, 2018, 159, pp.357-380. ⟨10.1016/j.ejmech.2018.10.003⟩. ⟨inserm-01980723⟩



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