First Evidence that Oligopyridines, Alpha Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-xL-Targeting Strategies.

Gloaguen C, Voisin-Chiret AS, Sopkova-de Oliveira Santos J, Fogha J, Gautier F, De Giorgi M, Burzicki G, Perato S, Pétigny-Lechartier C, Simonin-Le Jeune K, Brotin E, Goux D, N’Diaye M, Lambert B, Louis MH, Ligat L, Lopez F, Juin P, Bureau R, Rault S, Poulain L. Abstract – 13/01/2015

Journal of Medicinal Chemistry

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Apoptosis control defect such as the deregulation of Bcl-2 family members expression is frequently involved in chemoresistance. In ovarian carcinoma, we previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect cancer cells against apoptosis and their concomitant inhibition leads to massive apoptosis even in absence of chemotherapy. Whereas Bcl-xL inhibitors are now available Mcl-1 inhibition, required to sensitize cells to Bcl-xL-targeting strategies, remains problematic. In this context, we designed and synthesized oligopyridines potentially targeting Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells and implemented functional screening assay to evaluate their ability to sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies. We established structure-activity relationships and focused our attention on MR29072, named Pyridoclax. Surface plasmon resonance assay demonstrated that Pyridoclax directly binds to Mcl-1. Without cytotoxic activity as single agent, Pyridoclax induced apoptosis in combination with Bcl xL-targeting siRNA or with ABT-737 in ovarian, lung and mesothelioma cancer cells.