Cardiovascular diseases

Development of calcium pump activators for the treatment of heart failure

Heart failure (HF) is the leading cause of morbidity in the United States. Mortality rates remain high with only modest improvements in survival over the past decades, and current HF therapies only address peripheral symptoms without targeting directly the fundamental defects of the disease. This research aims to develop proprietary HF therapeutic candidates that target the calcium pump in the heart, a key molecular component whose diminished function is a hallmark of HF.  The team has developed highly promising small molecules that reverses HF in a clinically relevant model of the disease.

These small molecules target the cardiac sarcoplasmic reticulum calcium-ATPase (SERCA). SERCA plays an essential role in normal cardiac function, clearing cytosolic calcium needed to relax muscle cells in each heart beat (diastole). A key molecular dysfunction in HF usually involves insufficient SERCA expression, leading to SERCA inactivation and impaired calcium transport in the cardiomyocyte. SERCA is now widely recognized as a therapeutic target, and its activation results in improved cardiac function in HF models. It is crucial to develop alternative viable pharmacological approaches that have much improved chances of success, so we propose to develop small-molecule SERCA activators directed at the myocyte to restore normal function in the failing heart. Targeted pharmacological treatment using SERCA is completely novel and will fulfill an unmet medical need, since there are no drugs that target diastolic dysfunction in heart failure patients. 

The research team recently discovered and validated HF600, a high-quality hit that activates SERCA and stimulates intracellular calcium transport in human iPSC cardiomyocytes. The goal is now to pursue hit-to-lead optimization around HF600 to produce novel therapeutic candidates for the pharmacological treatment of HF. Two specific aims are currently being pursued in this project to test this hypothesis: (1) design and synthesize a series of pharmacologically viable SERCA activators built around the hit molecule HF600; (2) determine activity, therapeutic efficacy and microsomal stability of these novel SERCA activators. The therapeutic efficacy of these compounds will be tested using healthy and patient-derived diseased iPSC cardiomyocytes