Development of new cardioprotective drugs – Cardioprotection

We will perform the following tasks:
- synthesize enough quantity of our lead compound and of its back-up for extensive in vivo studies ;
- perform early ADME Tox studies and validate by an independent CRO the in vivo cardioprotective efficacy of our lead compound and its back-up;
- clarify the mechanism by which flavaglines display their cardioprotection.

We improved the synthesis of flavaglines and obtained enough product for extensive preclinical studies. We also clarified their mode of action by identifying the signaling pathways involved in cardioprotection.

Anthracyclines rank among the most effective anticancer drugs ever developed. However, their clinical use is limited by acute and chronic cardiotoxicities. We demonstrated that flavaglines exhibit a potent cardioprotection against anticancer chemotherapies. We have filed 2 patents related to this cardioprotection. We are validating our studies on mouse models of doxorubicin-induced cardiotoxicity to secure our current patent applications and to grant licenses to a pharmaceutical company.

1. Ribeiro N., et al. L. Flavaglines as Potent Anticancer and Cytoprotective Agents J Med Chem 55: 10064–10073 (2012).
2. Polier G., et al. The Natural Anti-cancer Compounds Rocaglamides Inhibit the Raf-MEK-ERK Pathway by Targeting Prohibitin 1 and 2. Chem. Biol. 19: 1093-104 (2012).

Anthracyclines, such as doxorubicin, epirubicin and daunorubicin, rank among the most effective anticancer drugs ever developed. However, their clinical use is limited by acute and chronic cardiotoxicities, which are dose related, cumulative and irreversible. The issue of this cardiotoxicity has not been solved so far and it is important to stress the current lack of proper prevention and treatment strategies.
We have for several years investigated the properties of synthetic analogues of natural compounds called flavaglines. We demonstrated that these molecules exhibit a potent cardioprotection against anticancer chemotherapies in cellular and in vivo models. We have filed 2 patents related to this cardioprotection. The objective of the current proposal is to validate our studies on mouse models of doxorubicin-induced cardiotoxicity to secure our current patent applications and to grant licenses to a pharmaceutical company. To this end, we will perform the following tasks:
- synthesize enough quantity of our lead compound and of its back-up for extensive in vivo studies ;
- perform early ADME Tox studies and validate by an independent CRO the in vivo cardioprotective efficacy of our lead compound and its back-up;
- clarify the mechanism by which flavaglines display their cardioprotection.

The issue of anthracycline cardiotoxicity has not been solved so far and it is also important to stress the current lack of proper prevention and treatment strategies. Thus, the development of novel strategies to prevent these side effects will provide tremendous impact on preventing anthracycline-induced cardiotoxicity, which represents a major market.