SBIR-STTR Award

Type 2 diabetes (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 ?-cell1-3. We have identified a novel SWELL1-mediated signaling pathway that regulates both insulin sensitivity and insulin secretion, whereby SWELL1 loss-of-function can both negatively regulate insulin signaling in target tissues4, 5 and insulin secretion from the pancreatic ?-cell6 – inducing a state of glucose intolerance4, 6 We have also identified a small molecule modulator, Smod1, as a lead compound that acutely inhibits SWELL1-mediated ICl,SWELL (> 90% inhibition) and induces compensatory SWELL1 protein up-regulation (3-fold). Smod1-mediated SWELL1 upregulation is associated with augmented adipocyte insulin signaling (1.5-fold) and enhanced ?-cell insulin secretion (up to 2-fold) in vitro. Smod1 normalizes both glucose tolerance and insulin sensitivity in obese, glucose intolerant mice and in the polygenic KKAy Type 2 diabetes mouse model. We propose that small molecule SWELL1 modulators may represent a “first-in-class” therapeutic approach to treat obesity- induced insulin resistance and Type 2 diabetes by augmenting both insulin sensitivity and secretion to improve glycemic control in diabetic patients. Importantly, Smod1 has no to very mild effects on non-obese euglycemic mice – emphasizing a very low risk of hypoglycemic events typically associated with other commonly used anti-diabetic therapies, including sulfonylureas, GLP-1 receptor agonists, and insulin. Finally, very infrequent Smod1 dosing (i.e once a month) may be sufficient to normalize systemic glycaemia in diabetic patients. The objectives of the current proposal are: 1. to establish the proof-of-concept of modulating SWELL1 signaling as a novel therapeutic approach for the treatment of T2D; and 2. To begin to develop a pipeline of SWELL1 modulators to treat T2D. AIM#1: Characterize the therapeutic effect of Smod1 in augmenting insulin sensitivity and secretion in T2D mouse models AIM#2: Explore Smod1 functional chemistry by characterizing Smod1 structural variants for modulation of SWELL1 activity in vitro and in vivo. AIM#3: Perform Absorption, Distribution, Metabolism, Elimination, and Toxicity studies (ADMET) studies on Smod1 and bioactive derivatives The results of Phase 1 will provide proof of concept for the pharmacological modulation of SWELL1 signaling for the treatment of T2D, and will provide an initial class of drug-like small molecules for further development of candidate molecules to ultimately take into humans in the form of a clinical trial for efficacy in T2D patients. We anticipate Phase 2 SBIR funding of drug development efforts as guided by success of the Phase 1 studies here.

Public Health Relevance Statement:
Project Narrative Diabetes and associated diseases are major health concerns in today's society. The proposed research is relevant to the mission of the NIDDK because it examines the therapeutic tractability of SWELL1 modulators for the treatment of Type 2 diabetes. 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.

Project Terms:
absorption; Acute; Adipocytes; Agonist; Antidiabetic Drugs; base; Beta Cell; Biological Assay; Chemistry; Clinical; Clinical Trials; Closure by clamp; Collaborations; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; diabetic patient; Disease; Dose; Drug Delivery Systems; drug development; Drug Kinetics; efficacy trial; Event; experimental study; Fatty acid glycerol esters; Funding; GLP-I receptor; Glucose; Glucose Clamp; Glucose Intolerance; glucose tolerance; glycemic control; Health; High Fat Diet; Hour; Human; Hyperglycemia; Hypoglycemia; Impairment; improved; In Vitro; in vitro activity; in vivo; in vivo Model; innovation; Insulin; Insulin Resistance; insulin secretion; insulin sensitivity; insulin sensitizing drugs; insulin signaling; intraperitoneal; Lead; Liver; loss of function; man; Measures; Mediating; Metabolism; Mission; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non obese; Non-Insulin-Dependent Diabetes Mellitus; novel; novel therapeutic intervention; novel therapeutics; Obesity; Oral; pancreatic juice; patch clamp; Pathogenesis; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; phase 1 study; Proteins; prototype; Regimen; Research; response; Risk; Rivers; Series; Signal Pathway; Signal Transduction; Skeletal Muscle; Small Business Innovation Research Grant; small molecule; Societies; Structure; Structure of beta Cell of islet; success; Sulfonylurea Compounds; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; treatment arm; Up-Regulation; Variant

More than 100 million Americans currently have diabetes or pre-diabetes, a condition that can lead to Type 2diabetes (T2D) within five years, and that vastly increases adverse cardiovascular events. T2D is characterizedby both a loss of insulin sensitivity of target tissues (fat, skeletal muscle, liver) and ultimately, impaired insulinsecretion 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-mediatedintracellular 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 toaugment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose toleranceby increasing insulin sensitivity and secretion T2D mouse models. SN-401 augments glucose uptake intoadipose tissue and myocardium, suppresses hepatic glucose production, and protects against hepaticsteatosis and hepatocyte damage. Combining cryo-EM with molecular docking simulations, and functionalstudies we have validated a structure-activity relationship (SAR) to generate novel SN-401 congeners with invivo anti-hyperglycemic activity in T2D models (SN-40X). We propose that small molecule SWELL1modulators may represent a first-in-class therapeutic approach to treat T2D and associatedcardiovascular disease by restoring SWELL1 signaling across multiple organ systems that aredysfunctional in T2D. Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) fromwhich to select one lead compound and one back-up to take into humans, with submission of anInvestigational 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 leadstructures.AIM 2: Perform in vivo dose-range finding toxicity studies, pre-clinical SN-40X dose-response andhead-to-head efficacy studies against SGLT2i, empagliflozin and GLP1a, liraglutideAIM 3: Manufacture the lead SN-40X compound under cGMP conditions required for all IND-enablingand 24-month stability studies and some Phase I clinical studies.

Public Health Relevance Statement:
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.

Project Terms: