Optimizing small molecule SWELL1-LRRC8 modulators to treat Type 2 diabetes

项目摘要/摘要 2型糖尿病(T2D)的特征是靶组织对胰岛素的敏感性丧失，最终受损 胰腺b细胞的胰岛素分泌。我们发现了一种新的SWELL1介导的信号通路 它同时调节胰岛素敏感性和胰岛素分泌，从而SWELL1功能丧失可以同时下调- 调节靶组织中的胰岛素信号，以及胰腺b细胞的胰岛素分泌。我们已经确定了一个 小分子调节剂DCPIB(更名为SN-401)作为结合SWELL1-LRRC8的工具化合物 作为分子伴侣，增强SWELL1的表达，质膜转运 和信号。在体内，SN-401通过增加胰岛素敏感性和分泌来正常化糖耐量。 小鼠T2D模型。SN-401还增加脂肪组织和心肌对葡萄糖的摄取，抑制 KKAy小鼠的肝脏葡萄糖生成，并保护喂食HFD的小鼠的肝脏脂肪变性。 我们认为小分子SWELL1调节剂代表了一种“一流”的治疗方法 通过恢复SWELL1信号跨多个 在T2D中器官系统功能失调。结合与其目标相结合的SN-401的最新低温电磁数据 SWELL1/LRRC8a分子对接模拟验证了构效关系(SAR) 基于一种方法，以产生具有增强或减少的靶上活性的新型SN-401同系物。这个 目标是：1.建立新合成药物的最佳给药方案和给药方式， 到目前为止合成的受SAR启发的SN-401同系物对T2D的治疗效果；2.评估 3.确定SN-401作用的主要组织部位(S)； 4.基于体外适配性和选择性的合成精制和优化引线 筛选和体内疗效研究。我们提出了以下具体目标 目的1：确定新型SAR给药的最佳给药方案、疗效及靶向组织(S) SN-401同系物。 目的#2：合成孔径雷达引导的SN-401的体内外优化和鉴定以鉴定临床前 引线结构。 这项提议寻求使用一种有效的化学生物学方法来扩展一条新的、 生物活性药理SWELL1信号调节剂治疗T2D代谢综合征 以及相关的疾病，最终以临床试验的形式在人类身上发挥作用。

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.