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Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes

优化小分子 SWELL1-LRRC8 调节剂治疗 2 型糖尿病

基本信息

批准号：
10617838
负责人：
Rajan Sah
金额：
$ 41.08万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617838
关键词：
Address Adipocytes Adipose tissue Antidiabetic Drugs B-Lymphocytes Beta Cell Binding Biology Blood Pressure Cardiac Cardiovascular system Cartoons Cell membrane Chemicals Chronic Complex Cryoelectron Microscopy Data Diabetes Mellitus Diabetes prevention Diabetic mouse Disease Docking Dose Drug Delivery Systems Event Fatty Liver Fatty acid glycerol esters Generations Glucose Glucose Intolerance Health Hepatic Human Hypoglycemia Impairment In Vitro Insulin Knockout Mice Laboratories Lead Lipids Liver Mediating Metabolic Metabolic syndrome Mission Modeling Molecular Molecular Chaperones Mus Myocardium Names National Institute of Diabetes and Digestive and Kidney Diseases Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Pharmaceutical Preparations Property Proteins Regimen Research Risk Series Signal Pathway Signal Transduction Site Skeletal Muscle Societies Structure Structure of beta Cell of islet Structure-Activity Relationship Sulfonylurea Compounds Testing Therapeutic Therapeutic Effect Tissues Treatment Efficacy Vertebral column blood glucose regulation body system cardiovascular effects diabetes pathogenesis efficacy clinical trial efficacy study euglycemia experimental study fasting glucose glucose production glucose tolerance glucose uptake heart function hemodynamics improved in vivo innovation insulin secretion insulin sensitivity insulin signaling insulin tolerance intraperitoneal islet loss of function man meter novel novel therapeutics pancreatic juice patch clamp pharmacologic pre-clinical protein expression response simulation small molecule therapeutic target tool trafficking

项目摘要

Project Summary/Abstract Type 2 diabetes (T2D) is characterized by both a loss of insulin sensitivity of target and ultimately, impaired insulin secretion from the pancreatic b-cell. We have identified a novel SWELL1-mediated signaling pathway that regulates both insulin sensitivity and insulin secretion, whereby SWELL1 loss-of-function can both down- regulate insulin signaling in target tissues, and insulin secretion from the pancreatic b-cell. 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, plasma membrane trafficking and signaling. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion in murine T2D models. SN-401 also augments glucose uptake into adipose tissue and myocardium, suppresses hepatic glucose production in KKAy mice, and protects against hepatic steatosis in HFD fed mice. We propose that small molecule SWELL1 modulators represent a “first-in-class” therapeutic approach to treat metabolic syndrome and associated diseases by restoring SWELL1 signaling across multiple organ system that are dysfunctional in T2D. Combining recent cryo-EM data of SN-401 bound to its target SWELL1/LRRC8a with molecular docking simulations we have validated a structure-activity relationship (SAR) based approach to generate novel SN-401 congeners with either enhanced or reduced on-target activity. The objectives are: 1. To establish the optimal dosing regimen and mode of administration for the newly synthesized, SAR-inspired SN-401 congeners synthesized to date to achieve a therapeutic effect for T2D; 2. To evaluate for putative beneficial cardiovascular effects; 3. To determine the primary tissue-site(s) of action of SN-401 in vivo; 4. SAR-based compound synthesis to refine and optimize the leads based on in vitro ADMET and selectivity screens, and efficacy studies in vivo. We propose the following specific AIMs AIM#1: Determine optimal dosing regimen, therapeutic effect and target tissue(s) of novel SAR-inspired SN-401 congeners. AIM#2: SAR-directed SN-401 optimization and characterization in vitro and in vivo to identify preclinical lead structures. This proposal seeks to use a validated chemical biology approach to expand a pipeline of novel, bioactive pharmacological SWELL1 signaling modulators for the treatment of T2D, metabolic syndrome and associated diseases to ultimately take into man in the form of a clinical trial for efficacy in humans.

项目总结/文摘