Targeting SWELL1 Signaling to Treat Obesity-Induced Type 2 Diabetes

项目摘要/摘要 目前有超过1亿美国人患有糖尿病或糖尿病前期，这种情况可能导致2型 糖尿病(T2D)在五年内发生，这极大地增加了心血管不良事件。T2D的特征是 由于靶组织(脂肪、骨骼肌、肝脏)对胰岛素敏感性的丧失，最终导致胰岛素受损 胰腺b细胞的分泌物。我们和其他人最近发现了一种新的离子通道信号复合体， 正向调节胰岛素介导的SWELL1/LRRC8a(富含亮氨酸重复序列的8a蛋白) 脂肪、骨骼肌和内皮的细胞内信号，胰腺β细胞的胰岛素分泌， 和全身性葡萄糖动态平衡。我们已经鉴定出一种小分子调节剂DCPIB(更名为SN- 401)，作为结合SWELL1-LRRC8复合体的工具化合物，并作为分子伴侣作用于 增强SWELL1的表达和质膜转运。在体内，SN-401可使糖耐量正常化 通过增加T2D小鼠模型对胰岛素的敏感性和分泌量。SN-401增加葡萄糖在体内的摄取 脂肪组织和心肌，抑制肝脏葡萄糖的产生，保护肝脏免受 脂肪变性和肝细胞损伤。将CRYO-EM与分子对接模拟相结合，以及 我们已经验证了结构-活性关系(SAR)，以生成新的SN-401同系物 T2D模型(SN-40X)的体内抗高血糖活性。我们提出小分子SWELL1 调节剂可能代表一种治疗T2D和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 T2D功能障碍。我们的总体目标是开发一系列领先的SN-401同类产品(SN-40X)，从 选择一种先导化合物和一种后备化合物用于人体，并提交 2023年第一季度向FDA提交研究用新药(IND)申请。 目的1：在合成孔径雷达引导下对SN-40X进行体外优化和表征以提纯临床前铅 结构。 目的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 SGLT2i、埃帕利福秦和GLP1a、利拉鲁肽的正面疗效研究 目标3：在所有支持IND的cGMP条件下制造铅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。

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.