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: 10081592
• 负责人: Daniel J Lerner
• 金额: $ 30.1万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081592
• 关键词: AKT2 gene; Ablation; Acids; Adipocytes; Adipose tissue; Adult; Affect; Aging; American; Back; Binding; Cell membrane; Chemicals; Chemistry; Cirrhosis; Clinical Research; Combined Modality Therapy; Complex; Cryoelectron Microscopy; Data; Development; Diabetes prevention; 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; 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; Mission; Modeling; Molecular; Molecular Chaperones; Mus; Myocardium; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Overnutrition; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Primary carcinoma of the liver cells; Process; Proteins; Research; Series; Signal Transduction; Site; Societies; Solubility; Structure; Structure of beta Cell of islet; Structure-Activity Relationship; Sucrose; Technology; Testing; 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; innovation; 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 therapeutics; phase 2 study; pre-clinical; response; simulation; small molecule; solid state; structured data; 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 signaling4, 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) 及其进展为晚期非酒精性脂肪性肝炎 (NASH) 健康问题日益严重，2015 年有 8,310 万美国人受到影响，预计这一数字将达到 1.009 亿 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疾病 NAFL-NASH 进展的贡献者，因此，治疗 T2D 和代谢性疾病的新治疗策略 预计该综合征也将使 NASH 受益，这是一个未得到满足的重大需求。我们和其他人最近发现了一个 新型离子通道信号复合物 SWELL1/LRRC8a（含有 8a 型蛋白的富含亮氨酸重复序列） 正向调节脂肪细胞胰岛素-PI3K-AKT2 信号传导4、胰腺 β 细胞的胰岛素分泌，以及 全身葡萄糖稳态。此外，功能失调的脂肪细胞 SWELL1 易患 NAFLD 和 肝细胞癌。我们已经确定了一种小分子调节剂 DCPIB（更名为 SN-401）作为 结合 SWELL1-LRRC8 复合物并作为药理学伴侣的工具化合物 增强 SWELL1 表达和质膜运输。在体内，SN-401 使葡萄糖耐量正常化 通过增加肥胖 T2D 小鼠模型的胰岛素敏感性和分泌。 SN-401 增强葡萄糖摄取 进入脂肪组织和心肌，抑制 KKAy 小鼠肝脏葡萄糖的产生，并保护 对抗 HFD 喂养小鼠的肝脂肪变性和肝细胞膨胀。我们建议小分子 SWELL1 调节剂可能代表治疗代谢综合征的“一流”治疗方法 通过恢复跨多个器官系统的 SWELL1 信号传导来治疗相关 NASH T2D 功能失调并导致 NASH 复杂的病理生理学 我们的总体目标是 开发 SN-401 同系物 (SN-40X) 的先导系列，从中选择一种先导化合物和一种备用化合物 于 2022 年第一季度向 FDA 提交研究性新药 (IND) 申请。 第一阶段目标： • AIM#1：SAR 指导的 SN-40X 体外优化和表征，以确定临床前先导药物 结构。 • AIM#2：完整的体外吸收、分布、代谢、排泄、毒性和选择性 研究。 第二阶段目标： • AIM#1：进行体内口服给药药代动力学和剂量范围发现毒性研究。 • AIM#2：针对 SN-40X 进行临床前剂量反应和头对头疗效研究 奥贝胆酸 (OCA) 用于减缓、阻止或逆转 NASH 的进展 • AIM#3：铅的完整固态表征、分析方法开发和验证 以及备用化学、制造和控制 (CMC) 途径。