First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x L -Targeting Strategies - Centre de recherche en cancérologie Nantes-Angers Unité Mixte de Recherche 892 Inserm - 6299 CNRS Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2015

First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x L -Targeting Strategies

Résumé

Apoptosis control defects such as the deregulation of Bcl-2 family member expression are 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 the 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 the Mcl-1 hydrophobic pocket, evaluated their capacity to inhibit Mcl-1 in live cells, and implemented a 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 when administered as a single agent, pyridoclax induced apoptosis in combination with Bcl-xL-targeting siRNA or with ABT-737 in ovarian, lung, and mesothelioma cancer cells
Fichier non déposé

Dates et versions

hal-02043913 , version 1 (21-02-2019)

Identifiants

Citer

Céline Gloaguen, Anne-Sophie Voisin-Chiret, Jana Sopkova-de Oliveira Santos, Jade Fogha, Fabien Gautier, et al.. First Evidence That Oligopyridines, α-Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-x L -Targeting Strategies. Journal of Medicinal Chemistry, 2015, 58 (4), pp.1644-1668. ⟨10.1021/jm500672y⟩. ⟨hal-02043913⟩
48 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More