Optimizing SWELL1 modulators to treat non-alcoholic steatohepatitis

优化 SWELL1 调节剂治疗非酒精性脂肪性肝炎

• 批准号: 10461207
• 负责人: Daniel J Lerner
• 金额: $ 108.93万
• 依托单位: SENSEION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461207
• 关键词: AKT2 gene; Ablation; Acids; Adipocytes; Adipose tissue; Affect; Aging; American; Back; Binding; Cell membrane; Chemicals; Chemistry; Cirrhosis; Clinical Research; Combined Modality Therapy; Complex; Cryoelectron Microscopy; Data; Development; Diabetic mouse; Diet; Direct Costs; Docking; Dose; Drug Delivery Systems; Drug Kinetics; Ensure; Evaluation; Excretory function; Exhibits; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Future; Glucose; Head; Health; Hepatic; Hepatocyte; High Fat Diet; Human; Hypoglycemic Agents; In Vitro; Insulin; Insulin Resistance; Investigational Drugs; Investigational New Drug Application; Ion Channel; Isoenzymes; Knockout Mice; Lead; Leucine-Rich Repeat; Liver Fibrosis; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Chaperones; Mus; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Overnutrition; Pathway interactions; Permeability; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Primary carcinoma of the liver cells; Process; Proteins; Series; Signal Transduction; Site; Small Business Innovation Research Grant; Solubility; Structure; Structure of beta Cell of islet; Structure-Activity Relationship; Sucrose; Technology; Therapeutic; Toxic effect; Validation; Vertebral column; absorption; analytical method; blood glucose regulation; body system; comparative efficacy; cytotoxicity; efficacy study; experimental study; glucose production; glucose tolerance; glucose uptake; impaired glucose tolerance; in vivo; insulin secretion; insulin sensitivity; lead series; method development; monolayer; multiple drug use; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; pancreatic juice; phase 2 study; pre-clinical; response; simulation; small molecule; solid state; tool; trafficking

Non-alcoholic fatty liver (NAFL) and its progression to advanced stage non-alcoholic steatohepatitis (NASH) is a growing health concern, with 83.1 million Americans affected in 2015, and projections to reach 100.9 million by 2030. Metabolic syndrome and Type 2 diabetes (T2D) are considered significant pathophysiological contributors to NAFL-NASH progression, therefore, novel therapeutic strategies to treat T2D and metabolic syndrome are also expected to benefit NASH, a significant unmet need. We, and others, recently identified a novel ion channel signaling complex, SWELL1/LRRC8a (Leucine rich repeat containing protein type 8a) that positively regulates adipocyte insulin-PI3K-AKT2 signaling 4, insulin secretion from pancreatic β-cells, and systemic glucose homeostasis. Moreover, dysfunctional adipocyte SWELL1 predisposes to NAFLD and hepatocellular carcinoma. 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 pharmacological chaperone to augment SWELL1 expression and plasma membrane trafficking. In vivo, SN-401 normalizes glucose tolerance by increasing insulin sensitivity and secretion in obese, T2D mouse models. SN-401 augments glucose uptake into adipose tissue and myocardium, suppresses hepatic glucose production in KKAy mice, and protects against hepatic steatosis and hepatocyte ballooning in HFD fed mice. We propose that small molecule SWELL1 modulators may represent a “first-in-class” therapeutic approach to treat metabolic syndrome and associated NASH by restoring SWELL1 signaling across multiple organ systems that are dysfunctional in T2D and contribute to the complex pathophysiology of NASH Our overall objective is to develop a lead series of SN-401 congeners (SN-40X) from which to select one lead and one back-up compound to take into humans, with submission of an Investigational New Drug (IND) application to the FDA in Q1 of 2022. Phase 1 AIMS: • AIM#1: SAR-directed SN-40X optimization and characterization in vitro to identify preclinical lead structures. • AIM#2: Complete in vitro absorption, distribution, metabolism, excretion, toxicity and selectivity studies. Phase 2 Aims: • AIM#1: Perform in vivo oral dosing pharmacokinetics and dose-range finding toxicity studies. • AIM#2: Perform pre-clinical SN-40X dose-response and head-to-head efficacy studies against obeticholic acid (OCA) for slowing progression of, halting, or reversing NASH • AIM#3: Complete solid-state characterization, analytical methods development & validation for lead and backup chemistry, manufacturing, and controls (CMC) pathways.

非酒精性脂肪肝（NAFL）及其发展为晚期非酒精性脂肪性肝炎（NASH）为 越来越多的健康问题，2015年有8310万美国人受到影响，预计将达到10090万 到2030年。代谢综合征和2型糖尿病（T2D）被认为是重要的病理生理学 因此，NAFL-NASH进展的贡献者是治疗T2D和代谢的新型治疗策略 综合征还有望使NASH受益，这是一个很大的未满足需求。我们和其他人最近确定了 新型离子通道信号传导复合物，Swell1/LRRC8A（含亮氨酸富含蛋白质型8a） 积极调节脂肪细胞胰岛素PI3K-AKT2信号4，胰腺β细胞的胰岛素分泌，以及 系统性葡萄糖稳态。此外，功能失调的脂肪细胞Swell1易于NAFLD和 肝细胞癌。我们已经确定了一个小分子调节剂DCPIB（更名为SN-401） 结合Swell1-LRC8复合物并用作药物链的工具化合物 增强Swell1表达和质膜运输。在体内，SN-401正常于葡萄糖耐受性 通过提高肥胖的胰岛素敏感性和分泌，T2D小鼠模型。 SN-401增强葡萄糖吸收 进入脂肪组织和心肌，抑制Kkay小鼠的肝葡萄糖产生，并保护 在HFD喂养的小鼠中反对肝脂肪变性和肝细胞气球。我们提出了小分子 Swell1调节剂可能代表一种治疗代谢综合征的“一流”治疗方法 通过恢复多个器官系统的Swell1信令，与NASH相关的NASH T2D功能失调，并有助于NASH的复杂病理生理学，我们的总体目标是 开发一个铅系列SN-401同类物（SN-40X），从中选择一个铅和一个备用化合物 在2022年第1季度向FDA提出调查新药（IND），以人类的身份加入人类。 第1阶段目的： •AIM＃1：SAR定向SN-40X优化和体外表征以识别临床前铅 结构。 •目标＃2：完整的体外抽象，分布，代谢，极端，毒性和选择性 研究。 第2阶段的目的： •目标＃1：进行体内口服药代动力学和剂量范围发现毒性研究。 •AIM＃2：进行临床前SN-40X剂量反应和面对面的效率研究 obeticholic Acid（OCA），用于减慢，停止或逆转NASH的进展 •AIM＃3：完整的固态表征，分析方法的开发和铅验证 以及备份化学，制造和控制（CMC）途径。