Preclinical evaluation of SERCA2 allosteric activators for pancreatic β-cell protection in diabetes.

The overall goal of this collaborative project between Neurodon and Indiana University School of Medicine is the development of compounds that will offer disease-modifying treatments for type 1 (T1D) and type 2 diabetes (T2D) mellitus, a sorely unmet need. In this initial STTR project, we will use our expertise in medicinal chemistry, cell biology, and diabetes pathophysiology to functionally test and chemically optimize a series of novel compounds that activate the sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA) pump. These compounds will be used to demonstrate initial efficacy to protect and improve insulin secretion in mouse and human pancreatic islets. T1D and T2D affect over 500 million people globally. Approved medications do not address the β cell dysfunction and destruction that are key drivers of both T1D and T2D pathophysiology. Maintaining intracellular Ca2+ homeostasis is critical to β cell function and survival by regulating the production and secretion of insulin and overall cellular health. We have shown that SERCA is deficient or dysfunctional in isolated islet β cells of organ donors with diabetes and in mouse and cell-based models of T1D and T2D. Aberrant SERCA function causes disrupted Ca2+ homeostasis, leading to activation of cellular stress pathways and eventual β cell loss in both T1D and T2D. In preliminary data, we have demonstrated that activation of SERCA by our novel small molecules protects and improves insulin secretion in diabetic β cell, representing a new, druggable target that has potential to offer to slow or halt diabetes pathogenesis. To take advantage of these insights, we will develop and optimize our proprietary series of novel SERCA activators for eventual treatment in patient populations. Our Aims are to (1) perform hit-to-lead and lead optimization assays on our novel series of SERCA2 activators to improve biological activity and physical properties; and (2) determine the efficacy of SERCA2 allosteric activators in modulating β cell survival under in vitro stress conditions and increasing ER Ca2+ levels and insulin secretion. These Aims will result in the delivery of 3-5 optimized lead compounds for further development and eventual clinical translation in future studies.