Non-alcoholic fatty liver (NAFL) and its progression to advanced stage non-alcoholic steatohepatitis (NASH) is a growing health concern, with 83.1 million Americans affected in 2015, and projections to reach 100.9 million by 2030. Metabolic syndrome and Type 2 diabetes (T2D) are considered significant pathophysiological contributors to NAFL-NASH progression, therefore, novel therapeutic strategies to treat T2D and metabolic syndrome are also expected to benefit NASH, a significant unmet need. We, and others, recently identified a novel ion channel signaling complex, SWELL1/LRRC8a (Leucine rich repeat containing protein type 8a) that positively regulates adipocyte insulin-PI3K-AKT2 signaling4, insulin secretion from pancreatic ?-cells, and systemic glucose homeostasis. Moreover, dysfunctional adipocyte SWELL1 predisposes to NAFLD and hepatocellular carcinoma. 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 pharmacological chaperone to augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion in obese, T2D mouse models. SN-401 augments glucose uptake into adipose tissue and myocardium, suppresses hepatic glucose production in KKAy mice, and protects against hepatic steatosis and hepatocyte ballooning in HFD fed mice. We propose that small molecule SWELL1 modulators may represent a first-in-class therapeutic approach to treat metabolic syndrome and associated NASH by restoring SWELL1 signaling across multiple organ systems that are dysfunctional in T2D and contribute to the complex pathophysiology of NASH Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) from which to select one lead and one back-up compound to take into humans, with submission of an Investigational New Drug (IND) application to the FDA in Q1 of 2022. Phase 1 AIMS: AIM#1: SAR-directed SN-40X optimization and characterization in vitro to identify preclinical lead structures. AIM#2: Complete in vitro absorption, distribution, metabolism, excretion, toxicity and selectivity studies. Phase 2 Aims: AIM#1: Perform in vivo oral dosing pharmacokinetics and dose-range finding toxicity studies. AIM#2: Perform pre-clinical SN-40X dose-response and head-to-head efficacy studies against obeticholic acid (OCA) for slowing progression of, halting, or reversing NASH AIM#3: Complete solid-state characterization, analytical methods development & validation for lead and backup chemistry, manufacturing, and controls (CMC) pathways.
Public Health Relevance Statement: Type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH) are major health concerns in todays 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 NASH and 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: Ablation; absorption; Acids; Adipocytes; Adipose tissue; Adult; Affect; Aging; AKT2 gene; American; analytical method; Back; Binding; blood glucose regulation; body system; Cell membrane; Chemicals; Chemistry; Cirrhosis; Clinical Research; Combined Modality Therapy; comparative efficacy; Complex; Cryoelectron Microscopy; cytotoxicity; Data; Development; Diabetes prevention; Diabetic mouse; Diet; Direct Costs; Docking; Dose; Drug Delivery Systems; Drug Kinetics; efficacy study; Ensure; Evaluation; Excretory function; Exhibits; experimental study; Fatty acid glycerol esters; Fatty Liver; Functional disorder; Future; glucose production; glucose tolerance; glucose uptake; Head; Health; Hepatic; Hepatocyte; High Fat Diet; Human; Hypoglycemic Agents; impaired glucose tolerance; In Vitro; in vivo; innovation; Insulin; Insulin Resistance; insulin secretion; insulin sensitivity; Investigational Drugs; Investigational New Drug Application; Ion Channel; Isoenzymes; Knockout Mice; Lead; lead series; Leucine-Rich Repeat; Liver Fibrosis; Metabolic syndrome; Metabolism; method development; Mission; Modeling; Molecular; Molecular Chaperones; monolayer; multiple drug use; Mus; Myocardium; National Institute of Diabetes and Digestive and Kidney Diseases; non-alcoholic fatty liver; non-alcoholic fatty liver disease; Non-Insulin-Dependent Diabetes Mellitus; nonalcoholic steatohepatitis; novel; novel therapeutics; Obesity; Oral; Overnutrition; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; phase 2 study; pre-clinical; Primary carcinoma of the liver cells; Process; Proteins; Research; response; Series; Signal Transduction; simulation; Site; small molecule; Societies; solid state; Solubility; Structure; Structure of beta Cell of islet; Structure-Activity Relationship; structured data; Sucrose; Technology; Testing; Therapeutic; tool; Toxic effect; trafficking; Validation; Vertebral column
