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

• 批准号: 10216501
• 负责人: Rajan Sah
• 金额: $ 42.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10216501
• 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

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/摘要 2型糖尿病（T2 D）的特征是目标胰岛素敏感性丧失，最终受损 胰腺B细胞分泌胰岛素。我们已经确定了一种新的SWELL 1介导的信号通路 调节胰岛素敏感性和胰岛素分泌，因此SWELL 1功能丧失可以降低- 调节靶组织中的胰岛素信号传导和胰腺B细胞的胰岛素分泌。我们已经确定了一 小分子调节剂DCPIB（重命名为SN-401）作为结合SWELL 1-LRRC 8的工具化合物 复合物，并作为分子伴侣增加SWELL 1表达，质膜运输 和信号。在体内，SN-401通过增加胰岛素敏感性和分泌使葡萄糖耐量正常化， 鼠T2 D模型。SN-401还增加脂肪组织和心肌的葡萄糖摄取，抑制 在KKAy小鼠中的肝葡萄糖产生，并且在HFD喂养的小鼠中保护免于肝脂肪变性。 我们认为小分子SWELL 1调节剂代表了“一流”的治疗方法 通过恢复SWELL 1信号转导治疗代谢综合征和相关疾病， 2型糖尿病患者的器官系统功能失调。结合SN-401与其靶点结合的最新冷冻EM数据 SWELL 1/LRRC 8a的分子对接模拟，我们已经验证了结构活性关系（SAR） 基于方法来产生具有增强或降低的靶向活性的新型SN-401同系物。的 目标是：1.为了建立新合成的药物的最佳给药方案和给药模式， 迄今为止合成的SAR启发的SN-401同源物以实现T2 D的治疗效果; 2.以评估 推定的有益心血管作用; 3.确定SN-401在体内的主要作用组织部位; 4.基于SAR的化合物合成，以基于体外ADMET和选择性的先导化合物进行精制和优化 筛选和体内功效研究。我们提出以下具体目标 目标#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。 目标#2：体外和体内SAR导向SN-401优化和表征，以确定临床前 主导结构。 该提案寻求使用经验证的化学生物学方法来扩展新的， 用于治疗T2 D代谢综合征的生物活性药理学SWELL 1信号传导调节剂 以及相关疾病，最终以临床试验的形式在人体内进行疗效试验。