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)

基本信息

批准号：
10455535
负责人：
Sihem Boudina
金额：
$ 59.92万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10455535
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 antagonist 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 interest liver inflammation 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 translational potential wound healing

项目摘要

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.

项目概要非酒精性脂肪性肝炎 (NASH) 是一种无症状、多因素、慢性肝纤维化疾病， NASH 会严重损害肝功能并影响很大一部分美国人。与饮食相关的肝脏肥胖，随着炎症、肝细胞变性和促纤维化而进展最终导致肝硬化和肝衰竭的反应目前尚无 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、减肥手术或移植肝。因此，对抗 NASH 的治疗措施的需求是巨大的，特别是考虑到 NASH 的数量由于肥胖和肥胖症的日益流行，全世界确诊的患者数量急剧增加该提案鉴定了 EphB 受体酪氨酸激酶及其跨膜 EphrinB 配体。作为治疗 NASH 的分子，EphB 受体与 EphrinB 配体的细胞间相互作用。启动双向信号级联反应，影响与 NASH 相关的多种生物过程纤维发生，包括细胞重塑、血管生成、迁移/增殖、上皮间质- 该项目的长期目标是开发 EphB/EphrinB 的有效抑制剂。我们将利用我们的早期研究成果来治疗 NASH。我们最近发现了一种有效的小分子 EphB/EphrinB 受体，可抑制小鼠炎症和纤维化 - 该应用的目的是优化我们的原型先导化合物。化合物以最大限度地发挥其抑制和药理学特性，用于体外治疗 NASH。分析中，我们的初步数据表明原型先导化合物可减少 TGF-β1 驱动的反式- 原代人肝星状细胞分化为促纤维化肌成纤维细胞，这一过程已知此外，我们的先导化合物的体内早期测试表明它可以减少 NASH 中的肝纤维化。在强大的早期阶段指导下，临床相关 NASH 小鼠模型中的脂肪变性、炎症和纤维化。关于我们的原型先导化合物解决肝纤维化和代谢问题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，以更好地了解我们的先导化合物的结构活性关系，并识别和表征更有效的相关类似物在目标 2 中，我们将展示具有改善的拮抗剂活性和药物样药理学特性的化学物质。测试并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据我们所知，逆转已建立的 NASH 模型中的肝纤维化和代谢功能障碍。这项工作首次研究了针对 EphB/EphrinB 信号传导的治疗潜力拟议的研究非常重要，因为它将推动 NASH 的治疗。 NASH 新型化合物，针对目前尚未引起人们兴趣或前沿的信号轴生物技术和制药行业。