Heart failure (HF) is a major cause of morbidity and mortality in the United States, accounting for 1 in 9 deaths and costing over $32 billion per year. Despite advancements in the clinical management of HF, the overall 5-year mortality rate has remained at over 50% for the past 10 years. This is, in part, due to current HF therapies being focused on addressing peripheral symptoms (e.g., blood pressure) instead of targeting the molecular defects within the cardiomyocyte directly. The Sarcoplasmic Reticulum (SR) Ca2+-ATPase (SERCA) enzyme is a membrane protein responsible for pumping two Ca2+ ions from the cytosol into the SR lumen to relax muscle cells (diastole), which is regulated endogenously by phospholamban (PLN). A key abnormality in HF involves insufficient SERCA expression and impaired PLN phosphorylation, synergistically leading to SERCA inactivation, and thus, decreased Ca2+ transport in the cardiomyocyte resulting in diastolic dysfunction. Previous studies have shown that reactivation of Ca2+ transport resulted in improved cardiac function in HF models, validating SERCA activation as a therapeutic approach for HF. Our preliminary studies led to the discovery and validation of HF600, a potent small molecule SERCA activator that stimulates intracellular Ca2+ transport to reverse calcium mishandling in diseased human cardiomyocytes (EC50= 2 μM), while also protecting the system against arrhythmia with no apparent long-term cardiotoxicity. Through data-driven, computer-aided, fragment-based drug design based on HF600, we are currently performing several hit-to-lead optimization structure-activity relationship campaigns to develop diverse classes of safe, effective, pharmacologically viable small molecule SERCA activators directed at cardiomyocytes to restore diastolic function in the failing heart. Our goal is to develop several small molecule, orally bioavailable HF therapeutic candidates for administration in both an acute hospital intervention and chronically reduced cardiac function setting.

Discovery and development of small molecule sarcoplasmic reticulum Ca2+-ATPase (SERCA) activators for the treatment of diastolic dysfunction

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