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: 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
• 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

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）是一种不对称的，多因素，慢性肝纤维化疾病， 急剧损害肝功能，并影响大部分美国人口。纳什是由 随着注射，肝细胞变性和促纤维化而进行的肝脏饮食相关的脂肪 最终导致肝硬化和肝衰竭的反应。 Nash没有FDA批准的治疗方法 疾病管理的唯一选择是生活方式，减肥手术或肝移植的变化。 因此，需要采取治疗措施来对抗NASH是巨大的，尤其是考虑到数量 由于肥胖和 糖尿病。该建议确定了EPHB受体酪氨酸激酶及其跨膜ephrinb配体 作为靶向治疗纳什的分子。 EPHB受体与ephrinb配体的细胞细胞相互作用 启动双向信号传导级联 纤维发生，包括细胞重塑，血管生成，迁移/增殖，上皮到间质 - 过渡和注射。该项目的长期目标是开发Ephb/ephrinb的潜在抑制剂 用于治疗NASH的信号。我们将利用我们的早期工作，该工作显示EPHB2促进肝 小鼠的炎症和纤维化，我们最近发现了潜在的小分子ephb/ephrinb受体 - 配体化学拮抗剂/抑制剂。该应用的目的是优化我们的原型铅 化合物以最大化其抑制性和药物特性，用于治疗NASH。在体外使用 测定，我们的初步数据表明原型铅化合物减少了TGF-β1驱动的反式。 将原代人肝星状细胞分化为促纤维化的肌纤维细胞，这一过程已知 有助于NASH的肝纤维化。此外，对体内铅化合物的早期测试表明它会减少 在临床上相关的NASH小鼠模型中，脂肪变性，感染和纤维化。在强大的早期指导下 关于我们原型效率的临床前数据导致化合物解决肝纤维化和代谢 与NASH相关的功能障碍，AIM 1将专注于医学化学努力，以更好地了解 铅化合物的结构活动关系，并识别和表征更多潜在的相关类似物 暴露于改善拮抗剂活性和类似药物的药物特性的化学物质。在目标2中，我们将 测试和验证我们的铅化合物的效率，以及所得的新的和改进的类似物的能力 逆转已建立的NASH模型中的肝纤维化和代谢功能障碍。据我们所知， 这项工作是第一个研究靶向Ephb/ephrinb信号传导的治疗潜力的工作 纳什的处理。拟议的研究非常重要，因为它将推进治疗 纳什小说的化合物靶向信号轴目前不符合或最前沿 生物技术和制药行业。