Development of prohibitin ligands to treat cancers, cardiac and immunological disorders

Over the last three decades, the scaffold proteins prohibitins-1 and -2 (PHB1/2) have emerged as key signaling proteins regulating a myriad of signaling pathways in health and diseases. Small molecules targeting PHBs display promising effects against several disease. With our collaborators we developed analogues of natural products belonging to the class of flavaglines that block the interaction between PHBs and C-RAF and, thereby, inhibit C-RAF-MEK-ERK signalling, which is critical to survival and proliferation of cancer cells.

We also demonstrated that these compounds protect the heart from the adverse effects of cancer chemotherapies involving anthracyclines. We showed that this cardioprotection is mediated by the activation of the mitochondrial PHB-STAT3 complex.

In addition to these lines of research, we also developed new PHB ligands belonging to the classes of spiro-oxindoles and triazines that respectively promote cardioprotection and modulate the biosynthesis of melanin in melanocytes. The structure-activity relationships of these new drugs and their detailed mechanism of action will also be presented.

Author(s): Laurent Désaubry

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