Project Summary/Abstract More than 100 million Americans currently have diabetes or pre-diabetes, a condition that can lead to Type 2 diabetes (T2D) within five years, and that vastly increases adverse cardiovascular events. T2D is characterized by both a loss of insulin sensitivity of target tissues (fat, skeletal muscle, liver) and ultimately, impaired insulin secretion from the pancreatic b-cell. We, and others, recently identified a novel ion channel signaling complex, SWELL1/LRRC8a (Leucine-rich repeat containing protein type 8a) that positively regulates insulin-mediated intracellular signaling in adipose, skeletal muscle, and endothelium, insulin secretion from pancreatic β-cells, and systemic glucose homeostasis. We have identified a small molecule modulator, DCPIB (renamed SN- 401), as a tool compound that binds the SWELL1-LRRC8 complex and functions as a molecular chaperone to augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion T2D mouse models. SN-401 augments glucose uptake into adipose tissue and myocardium, suppresses hepatic glucose production, and protects against hepatic steatosis and hepatocyte damage. Combining cryo-EM with molecular docking simulations, and functional studies we have validated a structure-activity relationship (SAR) to generate novel SN-401 congeners with in vivo anti-hyperglycemic activity in T2D models (SN-40X). We propose that small molecule SWELL1 modulators may represent a first-in-class therapeutic approach to treat T2D and associated cardiovascular disease by restoring SWELL1 signaling across multiple organ systems that are dysfunctional in T2D. Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) from which to select one lead compound and one back-up to take into humans, with submission of an Investigational New Drug (IND) application to the FDA in Q1 of 2023. AIM 1: SAR-directed SN-40X optimization and characterization in vitro to refine preclinical lead structures. AIM 2: Perform in vivo dose-range finding toxicity studies, pre-clinical SN-40X dose-response and head-to-head efficacy studies against SGLT2i, empagliflozin and GLP1a, liraglutide AIM 3: Manufacture the lead SN-40X compound under cGMP conditions required for all IND-enabling and 24-month stability studies and some Phase I clinical studies.

Project Narrative Type 2 diabetes (T2D) is a major health concern in today’s society. The proposed research is relevant to the mission of the NIDDK because it examines the therapeutic tractability of SWELL1 modulators (SN-40X) for the treatment of patients with Type 2 diabetes and impact on cardiovascular parameters. Exploring this therapeutic approach and testing a series of SWELL1 modulators will expand our understanding of novel therapeutic avenues and delineate an innovative target for the treatment and prevention of diabetes.