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：
10430129
负责人：
Rajan Sah
金额：
$ 40.84万
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/10430129
关键词：
Address Adipocytes Adipose tissue Antidiabetic Drugs B-Lymphocytes 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 Hot Spot Human Hypoglycemia Impairment In Vitro Insulin Knockout Mice Laboratories Lead Lipids Liver Mediating Metabolic Metabolic syndrome Mission Modeling Molecular Molecular Chaperones Mus Myocardium National Institute of Diabetes and Digestive and Kidney Diseases Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Pharmaceutical Preparations Pharmacology 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 Sum Testing Therapeutic Therapeutic Effect Tissues Treatment Efficacy Vertebral column base blood glucose regulation body system cardiovascular effects diabetes pathogenesis efficacy clinical trial efficacy study experimental study fasting glucose glucose production glucose tolerance glucose uptake heart function hemodynamics in vivo innovation insulin secretion insulin sensitivity insulin signaling insulin tolerance intraperitoneal islet loss of function man novel novel therapeutics pancreatic juice patch clamp 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.

项目概要/摘要 2 型糖尿病 (T2D) 的特点是目标胰岛素敏感性丧失并最终受损我们发现了一种新的 SWELL1 介导的信号通路。调节胰岛素敏感性和胰岛素分泌，因此 SWELL1 功能丧失会降低调节靶组织中的胰岛素信号传导以及胰腺 b 细胞的胰岛素分泌。小分子调节剂 DCPIB（更名为 SN-401），作为结合 SWELL1-LRRC8 的工具化合物复合物并作为分子伴侣增强 SWELL1 表达、质膜运输在体内，SN-401 通过增加胰岛素敏感性和分泌来使葡萄糖耐量正常化。小鼠 T2D 模型中，SN-401 还可以增加脂肪组织和心肌的葡萄糖摄取，抑制葡萄糖的摄取。 KKAy 小鼠的肝葡萄糖生成，并防止 HFD 喂养的小鼠发生肝脂肪变性。我们认为小分子 SWELL1 调节剂代表了“一流”的治疗方法通过恢复跨多个的 SWELL1 信号来治疗代谢综合征和相关疾病结合 SN-401 与其靶标结合的最新冷冻电镜数据。 SWELL1/LRRC8a 通过分子对接模拟，我们验证了构效关系 (SAR) 基于方法生成新型 SN-401 同系物，其目标活性增强或降低。目标是： 1. 建立新合成的最佳给药方案和给药方式，迄今为止合成的 SAR 启发的 SN-401 同系物可实现 T2D 的治疗效果；假定的有益心血管作用； 3. 确定 SN-401 体内作用的主要组织部位； 4. 基于 SAR 的化合物合成，基于体外 ADMET 和选择性来精炼和优化先导化合物我们提出以下具体目标。 AIM#1：确定新型 SAR 启发的最佳给药方案、治疗效果和靶组织 SN-401 同系物。 AIM#2：SAR 指导的 SN-401 体外和体内优化和表征，以识别临床前铅结构。该提案旨在使用经过验证的化学生物学方法来扩展新型、用于治疗 T2D、代谢综合征的生物活性药理学 SWELL1 信号调节剂以及相关疾病最终以临床试验的形式进入人体以验证其功效。