Small molecule antagonists targeting EphB receptors for the treatment of nonalcoholic steatohepatitis (NASH)

靶向 EphB 受体的小分子拮抗剂用于治疗非酒精性脂肪性肝炎 (NASH)

• 批准号: 10216710
• 负责人: Sihem Boudina
• 金额: $ 59.99万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216710
• 关键词: Adult; Affect; Animal Model; Animals; Binding; Biochemical; Biological Assay; Biological Availability; Biological Process; Biotechnology; Cardiovascular Diseases; Cell Communication; Cells; Chemicals; Chronic; Cirrhosis; Collagen; Coupled; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Disease Management; Drug Industry; Drug Kinetics; Effectiveness; Embryonic Development; EphB2 Receptor; Ephrin B Receptor; Ephrin Receptor EphB1; Ephrins; Excretory function; Exhibits; FDA approved; Fibrosis; Glucose; Goals; Healthcare; Hepatic; Hepatic Stellate Cell; Hepatocyte; High Density Lipoproteins; Homeostasis; Human; Hypertension; Hypertriglyceridemia; Impairment; In Vitro; Inflammation; Insulin; Lead; Life Style; Ligands; Liver; Liver Failure; Liver Fibrosis; Measures; Medical; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Molecular Weight; Mus; Myofibroblast; Obesity; Obesity Epidemic; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Play; Population; Primary carcinoma of the liver cells; Process; Property; Receptor Protein-Tyrosine Kinases; Research; Resolution; Rodent Model; Role; Signal Transduction; Signaling Molecule; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Transcript; United States; Work; absorption; analog; angiogenesis; bariatric surgery; base; chronic liver disease; chronic liver inflammation; clinical application; clinically relevant; combat; commercialization; comorbidity; effective therapy; effectiveness testing; efficacy testing; efficacy validation; epithelial to mesenchymal transition; experimental study; fibrogenesis; high throughput screening; improved; in vitro Assay; in vivo; inhibitor/antagonist; interest; liver transplantation; metabolic profile; migration; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; overexpression; phase III trial; pre-clinical; prevent; prototype; public health relevance; receptor; response; scaffold; small molecule; tissue injury; transdifferentiation; translational impact; wound healing

Project Summary Non-alcoholic steatohepatitis (NASH) is an asymptomatic, multifactorial, chronic liver fibrotic disease that drastically impairs hepatic function and affects a large proportion of the US population. NASH is caused by a diet-related fattening of the liver that progresses with inflammation, hepatocyte degeneration, and a pro-fibrotic response that ultimately results in cirrhosis and liver failure. There are no FDA-approved treatments for NASH and the only options for disease management are changes in lifestyle, bariatric surgery, or liver transplantation. The need for therapeutic measures to combat NASH is thus enormous, especially considering that the number of patients diagnosed worldwide is increasing dramatically due to the growing epidemic of obesity and diabetes. This proposal identifies the EphB receptor tyrosine kinases and their transmembrane EphrinB ligands as molecules to target for the treatment of NASH. Cell-cell interactions of EphB receptors with EphrinB ligands initiates bidirectional signaling cascades that can affect diverse biological processes relevant to NASH fibrogenesis including cellular remodelling, angiogenesis, migration/proliferation, epithelial-to-mesenchymal- transition, and inflammation. The long-term goal of this project is to develop a potent inhibitor of EphB/EphrinB signaling for the treatment of NASH. We will leverage our early work that shows EphB2 promotes hepatic inflammation and fibrosis in mice with our recent discovery of a potent small molecule EphB/EphrinB receptor- ligand chemical antagonist/inhibitor. The objective of this application is to optimize our prototype lead compound to maximize its inhibitory and pharmacological properties for the treatment of NASH. Using in vitro assays, our preliminary data indicates the prototype lead compound reduces TGF-β1-driven trans- differentiation of primary human hepatic stellate cells into pro-fibrotic myofibroblasts, a process known to contribute to liver fibrosis in NASH. Furthermore, early tests of our lead compound in vivo indicates it reduces steatosis, inflammation, and fibrosis in clinically relevant NASH mouse models. Guided by strong early-stage preclinical data on the efficacy of our prototype lead compound to resolve liver fibrosis and metabolic dysfunction associated with NASH, Aim 1 will focus on medicinal chemistry efforts to better understand the structure activity relationship of our lead compound and to identify and characterize more potent related analog chemicals that exhibit improved antagonist activity and drug-like pharmacological properties. In Aim 2 we will test and validate the efficacy of our lead compound and the resulting new and improved analogs for their ability to reverse liver fibrosis and metabolic dysfunction in established NASH models. To the best of our knowledge, this work is the first to investigate the therapeutic potential of targeting EphB/EphrinB signalling for the treatment of NASH. The proposed research is highly significant because it will advance for the treatment of NASH novel compounds that target a signaling axis not currently in the interest or forefront of the biotechnology and pharmaceutical industries.

项目摘要 非酒精性脂肪性肝炎（NASH）是一种无症状、多因素的慢性肝纤维化疾病， 严重损害肝功能并影响大部分美国人口。NASH是由一种 饮食相关的肝脏肥胖，伴随炎症、肝细胞变性和促纤维化进展 最终导致肝硬化和肝功能衰竭。没有FDA批准的NASH治疗方法 疾病管理的唯一选择是改变生活方式、减肥手术或肝移植。 因此，对对抗NASH的治疗措施的需求是巨大的，特别是考虑到NASH患者的数量 由于肥胖症的日益流行， 糖尿病该建议鉴定了EphB受体酪氨酸激酶及其跨膜EphrinB配体 作为治疗NASH的靶向分子。EphB受体与EphrinB配体的细胞-细胞相互作用 启动双向信号级联，影响NASH相关的多种生物学过程 纤维形成，包括细胞重塑、血管生成、迁移/增殖、上皮-间充质- 过渡和炎症。该项目的长期目标是开发一种有效的EphB/EphrinB抑制剂 用于治疗NASH的信号。我们将利用我们的早期工作，表明EphB 2促进肝脏 我们最近发现了一种有效的小分子EphB/EphrinB受体， 配体化学拮抗剂/抑制剂。此应用程序的目的是优化我们的原型铅 本发明还涉及化合物以使其用于治疗NASH的抑制和药理学性质最大化。使用体外 我们的初步数据表明，原型先导化合物减少了TGF-β1驱动的反式- 原代人肝星状细胞向促纤维化肌成纤维细胞的分化， 导致NASH的肝纤维化。此外，我们的先导化合物在体内的早期试验表明， 脂肪变性、炎症和纤维化。以强有力的前期引导 关于我们的原型先导化合物解决肝纤维化和代谢紊乱的功效的临床前数据 与NASH相关的功能障碍，目标1将侧重于药物化学工作，以更好地了解 我们先导化合物的构效关系以及鉴定和表征更有效的相关类似物 显示出改善的拮抗剂活性和药物样药理学性质的化学品。在目标2中， 测试和验证我们的先导化合物的功效以及由此产生的新的和改进的类似物的能力， 逆转NASH模型中的肝纤维化和代谢功能障碍。据我们所知， 这项工作是第一次研究靶向EphB/EphrinB信号转导治疗糖尿病的潜力。 NASH的治疗这项研究非常重要，因为它将促进治疗 靶向信号传导轴的NASH新化合物目前不是研究的兴趣或前沿。 生物技术和制药业。