Parkin activators for cardioprotective therapies

Myocardial infarction followed by left ventricular remodeling is the leading cause of heart failure (HF). Current therapies are inadequate to modulate adverse remodeling and prevent subsequent cardiac failures. As such there is a critical unmet need to identify new therapies. There is strong evidence suggesting that mitophagy exerts cardioprotective effects following infarction (MI) and that impaired mitochondrial biogenesis contributes to HF. Mitochondrial dysfunction reduces energy production, releasing harmful reactive oxygen species and proinflammatory molecules, which contribute to the ischemic reperfusion injury leading to HF. Regulated and selective clearance of damaged mitochondria via mitophagy orchestrated by PINK1 kinase and Parkin ubiquitin ligase, is a key mitochondrial quality control mechanism. Moreover, Parkin has been shown to regulate mitogenesis by ubiquitinating and degrading PARIS, a key repressor of PGC1, the positive regulator of mitogenesis. For these reasons, intervention to promote the Parkin-mediated mitochondrial quality control pathway is a promising therapeutic strategy to prevent or ameliorate post-MI heart failure. Parkin exists in an auto-inhibited state in cells and is activated by PINK1. Progenra utilized a novel TR-FRET assay and discovered small molecules that bind and activate Parkin selectively. Consistent with Parkin activation, these Parkin activator compounds (PACs) degrade Parkin substrates (e.g. PARIS) and potently upregulate mitophagy in various cell models. In addition, PACs promoted mitochondrial turnover in Mitotimer mice after permanent coronary artery ligation (PCAL). Most important, administration of PAC (1mg/kg) in mice after PCAL resulted in profound mitigation of adverse cardiac remodeling and fibrosis leading to improved cardiac function and survival of wild type mice after PCAL. Thus, we have established preliminary in vivo proof of cardioprotection by PAC. In this phase I proposal, we will use adult rat primary cardiomyocytes as well as clinically relevant diet-induced obesity mouse model subjected to PCAL to further evaluate and characterize the cardioprotective role of PACs. Improvements in cardiac performance, survival, fibrosis, mitochondrial composition and function, and the landscape of Parkin-mediated ubiquitylome will be determined. In Phase II, we will evaluate long-term safety and efficacy of PACs in rodent and swine models, particularly their ability to improve cardiac functions post-MI, attenuate adverse remodeling, and suppress inflammation and fibrosis driven by innate immunity. The ultimate goal is the development of Parkin activator that can be used to treat post-MI reperfusion injury and prevent heart failure.