Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes

项目总结/摘要 目前有超过1亿美国人患有糖尿病或糖尿病前期，这种情况可能导致2型糖尿病 糖尿病（T2 D）在五年内，这大大增加了不良心血管事件。T2 D的特点是 由于靶组织（脂肪、骨骼肌、肝脏）的胰岛素敏感性丧失， 胰腺B细胞分泌物。我们和其他人最近发现了一种新的离子通道信号复合物， SWELL 1/LRRC 8a（富含亮氨酸重复序列的蛋白质8a型），正调节胰岛素介导的 脂肪、骨骼肌和内皮中的细胞内信号传导，胰腺β细胞的胰岛素分泌， 和全身葡萄糖稳态。我们已经鉴定了一种小分子调节剂DCPIB（重命名为SN-1）。 401），作为结合SWELL 1-LRRC 8复合物的工具化合物，并作为分子伴侣发挥作用， 增加SWELL 1表达和质膜运输。在体内，SN-401使葡萄糖耐量正常化 通过增加T2 D小鼠模型的胰岛素敏感性和分泌。SN-401增加葡萄糖摄取， 脂肪组织和心肌，抑制肝脏葡萄糖的产生，并保护肝脏 脂肪变性和肝细胞损伤。将冷冻EM与分子对接模拟相结合， 我们已经验证了构效关系（SAR），以产生新的SN-401同系物， T2 D模型中的体内抗高血糖活性（SN-40 X）。我们认为小分子SWELL 1 调节剂可以代表治疗T2 D和相关疾病的一流治疗方法。 通过恢复跨多个器官系统的SWELL 1信号传导， 2型糖尿病的功能障碍我们的总体目标是开发一系列SN-401同系物（SN-40 X）， 选择一种先导化合物和一种备用化合物进入人体， 2023年第一季度向FDA提交研究性新药（IND）申请。 目的1：SAR导向的SN-40 X体外优化和表征，以优化临床前电极导线 结构. 目的2：进行体内剂量范围探索毒性研究、临床前SN-40 X剂量反应和 针对SGLT 2 i、恩格列净和GLP 1a、利拉鲁肽的头对头疗效研究 目的3：在所有IND启用所需的cGMP条件下生产SN-40 X先导化合物 以及24个月稳定性研究和一些I期临床研究。

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.