Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1

Abstract

Introduction

With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1.

Results

A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234.

Conclusion

Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.

Graphical Abstract

Keywords:

• drug repurposing
• Mcl-1
• Deferasirox
• NMR
• docking
• dynamics

Acknowledgments

This work has been partially supported by Normandie Université (NU), the Région Normandie, the Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (URN), INSA Rouen Normandie, Labex SynOrg (ANR-11-LABX-0029), Innovation Chimie Carnot (I2C). Part of this work was performed using computing resources of CRIANN (Normandy, France) as well as the European Community (FEDER) for the molecular modeling software.

We thank Christophe Denoyelle and Emilie Brotin from ImpedanCELL platform for real-time imaging experiments. The IncuCyte S3 device was acquired thanks to the support of the French State and the ‘Normandy County Council’ (Contrat de Plan Etat Région - CPER INNOVONS). This work was also supported by the “Conseil Régional de Basse Normandie” and European Union (The ONCOTHERA European project “Normandy Network for innovative therapeutics in oncology” which is co-funded by the Normandy County Council, the European Union within the framework of the Operational Programme ERDF/ESF 2014-2020), by the French State (CPER Innovons 2), the University of Caen Normandie and Inserm. HP is a recipient of a doctoral fellowship from the French Ministry for Higher Education and Research.

Author Contributions

ABA, ASVC, MS and HO conceived the studies; ABA and MS performed NMR studies; DR and LC have carried out the production and purification of the labeled Mcl-1^172−327 domain; HP, LW and LP have carried out bioassays; MJ carried out FPA experiments; MB, GC and JSO performed docking and dynamics simulations; ABA, JSO, and MS wrote the article with corrections from all co-authors. So, all authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.