Citation
- Authors: Gloaguen, C., Voisin-Chiret, A. S., Sopkova-de Oliveira Santos, J., Fogha, J., Gautier, F., De Giorgi, M., Burzicki, G., Perato, S., Petigny-Lechartier, C., Simonin-Le Jeune, K., Brotin, E., Goux, D., N'Diaye, M., Lambert, B., Louis, M. H., Ligat, L., Lopez, F., Juin, P., Bureau, R., Rault, S., Poulain, L.
- Year: 2015
- Journal: J Med Chem 58 1644-68
- Applications: in vitro / siRNA / INTERFERin
- Cell types:
- Name: SK-OV-3
Description: Human ovary carcinoma cells
Known as: SKOV3, SKOV-3 - Name: A2780
- Name: A549
Description: Human lung carcinoma cells, type II pneumocytes
Known as: A-549 - Name: IGROV1-R10
- Name: MSTO-211H
Description: Human lung mesothelioma cells
- Name: SK-OV-3
Method
10-30 nM siRNA.
Abstract
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.