2. Academic Validation
  3. First evidence that oligopyridines, α-helix foldamers, inhibit Mcl-1 and sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies

First evidence that oligopyridines, α-helix foldamers, inhibit Mcl-1 and sensitize ovarian carcinoma cells to Bcl-xL-targeting strategies

  • J Med Chem. 2015 Feb 26;58(4):1644-68. doi: 10.1021/jm500672y.
Céline Gloaguen 1,  Anne Sophie Voisin-Chiret,  Jana Sopkova-de Oliveira Santos,  Jade Fogha,  Fabien Gautier,  Marcella De Giorgi,  Grégory Burzicki,  Serge Perato,  Cécile Pétigny-Lechartier,  Karin Simonin-Le Jeune,  Emilie Brotin,  Didier Goux,  Monique N'Diaye,  Bernard Lambert,  Marie-Hélène Louis,  Laetitia Ligat,  Frédéric Lopez,  Philippe Juin,  Ronan Bureau,  Sylvain Rault,  Laurent Poulain
Affiliations

Affiliation

  • 1 Normandie Université , 14032 Caen, France.
PMID: 25585174 DOI: 10.1021/jm500672y
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.

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