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Protein-Protein Interactions

Protein-protein interactions (or PPIs) play a fundamental role in the signal transduction regulating many cellular functions such as programmed cell death. Any disturbance to the apoptosis is linked to the phenomena of cancer and/or escape from conventional forms of chemo- and radiation therapy. The process of apoptosis is controlled by a diversity of signal pathways and involved in particular proteins from the Bcl-2 family (pro-apoptotics [Bax, Bak] and anti-apoptotics [Mcl-1, Bcl-2, Bcl-xL]) which interact via a helicoidal BH3 crucial domain. The anti-apoptotic proteins Bcl-xL and Mcl-1 work together to protect the cancer ovarian cells from the apoptosis and their simultaneous inhibition results in the death of the chemo-resistant cells. The inhibition of Bcl-xL can be obtained by using Navitoclax. However, the inhibition of Mcl-1 remains problematic and the development of useable clinical pharmacological tools therefore represents a major challenge, since the protein has been shown to be a priority therapeutic target in many tumour locations.
The CERMN’s research is interested in designing BH3-mimetic PPI-disruptive foldamers in the treatment of chemo-resistant ovarian cancers. The synthesis of a chemical library containing BH3-mimetic foldamers, characterization of foldamers by X-ray diffraction radiocrystallography and by NMR and their biological evaluation towards ovarian cancer cell lines led to select Pyridoclax for which the potent pro-apoptotic activity is directly linked to the inhibition of the Mcl-1 anti-apoptotic protein. Pyridoclax is also currently under preclinical investigation.

Major publications

Gloaguen, C. et al. First Evidence that Oligopyridines, Alpha Helix Foldamers, Inhibit Mcl-1 and Sensitize Ovarian Carcinoma Cells to Bcl-xL-Targeting Strategies. J. Med. Chem. 2015, 58, 1644-1668.

Perato, S. et al. Conformation control of abiotic alpha-helical foldamers. J. Chem. Inf. Model. 2013, 53, 2671-2680

De Giorgi, M. et al. Targeting the BH3 domain of Bcl-2 family proteins. A brief history from natural products to foldamers as promising cancer therapeutic avenues. Curr. Med. Chem. 2013, 20(24), 2964-2978.

Voisin-Chiret, A.S. and Rault, S. The use of halo (het) arylboronic acids and esters to achieve syntheses of garlands as mimics of alpha helices able to disrupt protein-protein interactions. Pure Appl. Chem. 2012, 84, 2467-2478.

Sopkovà-de Oliveira Santos, J. et al. Structural characterisations of oligopyridyl foldamers, alpha helix mimetics. J. Chem. Inf. Model. 2012, 52, 429-439.

Major collaborations

  • Equipe Analyse et Modélisation, COBRA UMR 6014 · Rouen, Pr H.Oulyadi et Dr M. Sebban.
  • Unité BioTICLA, UMR1199 Inserm, Centre de Lutte Contre le Cancer F. Baclesse · Caen, Dr L. Poulain.
  • CRCNA, UMR892 Inserm · Nantes, Dr P. Juin et Dr F. Gautier.
  • Plateforme Protéomique, UMR1037 Inserm, Pôle Technologique du Centre de Recherches en Cancérologie de Toulouse · Toulouse, Dr F.Lopez et Dr L. Ligat.
  • Groupe Mémoire et Plasticité comportementale · Caen, Pr M. Boulouard et Pr T. Freret.
  • Equipe « Structure et Dynamique des Biomolécules », Université Pierre et Marie Curie, Universités Sorbonne, UMR CNRS 7203 ERL Inserm U1057 · Paris, Dr L. Carlier

Financial supports


 

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Last update : July 4, 2016


CONTACT

Pr Anne-Sophie Voisin-Chiret
+33 (0)2 31 56 68 04
anne-sophie.voisin@unicaen.fr

Université de Caen Normandie
CERMN Centre détudes et de recherche sur le médicament de Normandie
Boulevard Becquerel | 14032 Caen Cedex | France