Syracuse

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

Archive ouverte

Hedir, Siham | de Giorgi, Marcella | Fogha, Jade | de Pascale, Martina | Weiswald, Louis-Bastien | Brotin, Emilie | Marekha, Bogdan | Denoyelle, Christophe | Denis, Camille | Suzanne, Peggy | Gautier, Fabien | Juin, Philippe | Ligat, Laetitia | Lopez, Frédéric | Carlier, Ludovic | Legay, Rémi | Bureau, Ronan | Rault, Sylvain | Poulain, Laurent | Sopkova-de Oliveira Santos, Jana | Voisin-Chiret, Anne-Sophie

Edité par CCSD ; Elsevier -

International audience. 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.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion