Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes

靶向 SWELL1 信号传导治疗肥胖引起的 2 型糖尿病

基本信息

批准号：
10490426
负责人：
Daniel J Lerner
金额：
$ 99.09万
依托单位：
SENSEION THERAPEUTICS, INC.
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：
2021-09-17 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10490426
关键词：
Ablation Adipocytes Adipose tissue American Back Binding Biological Markers Blood Pressure Body Composition Cardiac Cardiovascular Diseases Cardiovascular system Cell membrane Chemicals Chronic Clinical Research Collaborations Complex Contracts Cryoelectron Microscopy Cyclic GMP Data Diabetes Mellitus Diabetes prevention Diabetic mouse Disease Docking Dose Drug Delivery Systems Endothelium Ensure Evaluation Event Fatty Liver Fatty acid glycerol esters Fibrosis Glucose Head Health Hepatic Hepatocyte High Fat Diet Human Hypoglycemic Agents Impairment In Vitro Insulin Insulin Resistance Investigational Drugs Investigational New Drug Application Ion Channel Lead Leucine-Rich Repeat Liver Mediating Metabolic Metabolic syndrome Mission Modeling Molecular Molecular Chaperones Mus Myocardium National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Overnutrition Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Prediabetes syndrome Proteins Regimen Research Series Signal Induction Signal Transduction Site Skeletal Muscle Societies Structure Structure of beta Cell of islet Structure-Activity Relationship Testing Therapeutic Tissues Toxic effect Vertebral column Work blood glucose regulation body system cardiovascular disorder risk comparative efficacy diabetes pathogenesis efficacy study experimental study fasting glucose glucose production glucose tolerance glucose uptake glycemic control heart function hemodynamics impaired glucose tolerance in vivo innovation insulin secretion insulin sensitivity insulin tolerance islet lead series liraglutide multiple drug use nonalcoholic steatohepatitis novel novel therapeutics pancreatic juice pre-clinical preclinical efficacy protein expression response simulation skeletal small molecule tool trafficking

项目摘要

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.

项目概要/摘要目前有超过 1 亿美国人患有糖尿病或糖尿病前期，这种疾病可能导致 2 型糖尿病五年内发生糖尿病（T2D），并且 T2D 的不良心血管事件大大增加。由于靶组织（脂肪、骨骼肌、肝脏）胰岛素敏感性丧失以及最终胰岛素受损我们和其他人最近发现了一种新型离子通道信号复合物， SWELL1/LRRC8a（富含亮氨酸重复序列，含有 8a 型蛋白），可正向调节胰岛素介导的脂肪、骨骼肌和内皮细胞内的信号传导、胰腺 β 细胞的胰岛素分泌、我们已经确定了一种小分子调节剂 DCPIB（更名为 SN-）。 401)，作为一种工具化合物，结合 SWELL1-LRRC8 复合物并作为分子伴侣发挥作用 SN-401 增强 SWELL1 表达和质膜运输，使葡萄糖耐量正常化。通过增加胰岛素敏感性和分泌，SN-401 增加了 T2D 小鼠模型的葡萄糖摄取。脂肪组织和心肌，抑制肝脏葡萄糖的产生，并预防肝病将冷冻电镜与分子对接模拟和功能相结合。研究中，我们验证了结构活性关系 (SAR)，以生成新型 SN-401 同系物我们提出小分子 SWELL1 在 T2D 模型中具有体内抗高血糖活性（SN-40X）。调节剂可能代表治疗 T2D 及相关疾病的一流治疗方法通过恢复跨多个器官系统的 SWELL1 信号来治疗心血管疾病我们的总体目标是开发 SN-401 同系物 (SN-40X) 的先导系列。选择一种先导化合物和一种备用化合物用于人体，并提交一份于 2023 年第一季度向 FDA 提交研究性新药 (IND) 申请。目标 1：SAR 指导的 SN-40X 体外优化和表征，以完善临床前先导药物结构。目标 2：进行体内剂量范围发现毒性研究、临床前 SN-40X 剂量反应和针对 SGLT2i、恩格列净和 GLP1a、利拉鲁肽的头对头疗效研究目标 3：在所有 IND 所需的 cGMP 条件下制造先导 SN-40X 化合物以及24个月的稳定性研究和一些I期临床研究。