The overall goal of this collaborative project between Neurodon and Indiana University School of Medicine is thedevelopment 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 novelcompounds that activate the sarco/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA) pump. Thesecompounds will be used to demonstrate initial efficacy to protect and improve insulin secretion in mouse andhuman pancreatic islets. T1D and T2D affect over 500 million people globally. Approved medications do notaddress 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 productionand secretion of insulin and overall cellular health. We have shown that SERCA is deficient or dysfunctional inisolated islet β cells of organ donors with diabetes and in mouse and cell-based models of T1D and T2D. AberrantSERCA function causes disrupted Ca2+ homeostasis, leading to activation of cellular stress pathways andeventual β cell loss in both T1D and T2D. In preliminary data, we have demonstrated that activation of SERCAby 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 theseinsights, we will develop and optimize our proprietary series of novel SERCA activators for eventual treatmentin patient populations. Our Aims are to (1) perform hit-to-lead and lead optimization assays on our novel seriesof SERCA2 activators to improve biological activity and physical properties; and (2) determine the efficacy ofSERCA2 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 furtherdevelopment and eventual clinical translation in future studies.
Public Health Relevance Statement: Disrupted intracellular calcium (Ca2+) homeostasis has been shown to be responsible for activation of stress
pathways that lead to β-cell destruction in both type 1 (T1D) and type 2 diabetes (T2D). Our small molecules
selectively activate the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump, restore Ca2+ homeostasis,
and have demonstrated the ability to protect β-cells and improve insulin secretion in human and animal models
of T1D and T2D. In this proposal, we will perform optimization activities to deliver confirmed lead compounds to
enable new therapeutic candidates for T1D and T2D.
Project Terms: <β-cell><β-cells><βCell> | | | 