Grant: Operating Grant: Industry-partnered Collaborative Research

Every 7 minutes someone suffers from a heart attack in Canada. Despite medical treatment such as coronary artery dilatation or surgery, cardiac injury is irreversible. Loss of heart muscle following a myocardial infarct (heart attack) will ultimately result in cardiac pump failure and increased risk of death. Therefore, new drugs that could induce the heart's resistance to heart attack injury would be of great clinical importance. Our studies have identified a naturally occurring chemical compound, Celastrol, isolated from a medicinal plant that demonstrates potent cprotective effects in isolated cardiac cell culture and in an animal model of heart attack. We found that Celastrol, targeting an important protein named HSP90, has the capacity to activate protective signals that defend the heart against infarct damage. Based on these findings, we screened commercially available drugs with chemical structure similarities with Celastrol, and other compounds known to target various regions of the HSP90 protein. Our preliminary tests suggest that only compounds structurally similar to Celastrol and targeting the same region of HSP90 as Celastrol are efficient in inducing significant protection. We hereby propose with our industry partner NEOMED and its drug discovery experts to extend and validate our preliminary screens with proprietary molecules in order to identify and develop a new, potent and safe class of drug for human use. We will study and compare our partners test molecules in cell cultures to validate and unravel with precision the molecular pathways activating cardiac cell protection. Information from our study will also allow chemists to optimize various chemical parameters of compounds to obtain drugs that perform in intra-venous formulation, and ultimately this project will set the stage to deliver a new class of compound that could help save the heart of patients having a heart attack.