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: 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
• 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

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.

项目摘要/摘要 2型糖尿病（T2D）的特征是靶标的胰岛素敏感性丧失和最终受损 胰腺B细胞的胰岛素分泌。我们已经确定了一种新型的Swell1介导的信号通路 这既调节胰岛素敏感性又调节胰岛素分泌，从而使1个功能丧失都可以降低 调节靶时间中的胰岛素信号传导，以及胰腺B细胞的胰岛素分泌。我们已经确定了 小分子调节剂DCPIB（重命名为SN-401），作为结合Swell1-lrrc8的工具化合物 复杂并用作分子伴侣，以增强Swell1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在 鼠T2D型号。 SN-401还增加了葡萄糖吸收到脂肪组织和心肌中，抑制 KKAY小鼠中的肝葡萄糖产生，并预防HFD Fed小鼠中的肝脂肪变性。 我们建议小分子Swell1调节剂代表一种“一流”的治疗方法 通过恢复多个swell1信号来治疗代谢综合征和相关疾病 T2D中功能失调的器官系统。结合了SN-401的最新冷冻EM数据绑定到其目标 swell1/lrrc8a带有分子对接模拟的swell1/lrrc8a我们已经验证了结构活性关系（SAR） 基于基于增强或减少靶向活动的新型SN-401同源物的方法。这 目标是：1。建立新合成的最佳给药方案和管理模式， 迄今为止，SAR为灵感的SN-401同源物合成以实现T2D的治疗作用； 2。评估 推定的有益心血管效应； 3。确定SN-401在体内作用的主要组织位置； 4。基于SAR的化合物合成以根据体外ADMET和选择性来完善和优化铅 筛选和体内效率研究。我们提出以下特定目标 AIM＃1：确定新型SAR-Insprip的最佳给药方案，治疗效果和靶组织 SN-401同类物。 AIM＃2：SAR定向SN-401在体外和体内优化和表征以识别临床前 铅结构。 该提案试图使用经过验证的化学生物学方法扩展新颖的管道， 用于治疗T2D代谢综合征的生物活性药物Swell1信号调节剂 以及相关的疾病，最终以人类效率的临床试验形式加入人。