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

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，并影响到很大一部分美国人口。NASH由一种 与饮食有关的肝脏肥大，进展为炎症、肝细胞变性和促肝纤维化 最终导致肝硬变和肝衰竭的反应。目前还没有FDA批准的NASH治疗方法 而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，防治纳什的治疗措施的必要性是巨大的，特别是考虑到 由于肥胖和肥胖的日益流行，全世界确诊的患者比例正在急剧增加 糖尿病。这项建议确定了EphB受体酪氨酸激酶及其跨膜EphinB配体 作为治疗NASH的靶向分子。EphB受体与EphinB配体的细胞间相互作用 启动双向信号级联反应，可影响与NASH相关的各种生物过程 纤维化形成包括细胞重塑、血管生成、迁移/增殖、上皮向间充质转化。 过渡期和炎症。该项目的长期目标是开发一种有效的EphB/EPhinB抑制剂 治疗NASH的信号。我们将利用我们早期的工作，表明EphB2促进肝脏 小鼠的炎症和纤维化与我们最近发现的一种有效的小分子EphB/EwitinB受体- 配体化学拮抗剂/抑制剂。此应用程序目标是优化我们的原型Lead 化合物，以最大限度地发挥其抑制和治疗NASH的药理作用。在体外使用 分析，我们的初步数据表明，原型先导化合物减少转化生长因子-β1驱动的反式- 原代人肝星状细胞分化为促纤维化的肌成纤维细胞，这一过程已知 会导致NASH的肝纤维化。此外，对我们体内先导化合物的早期测试表明，它可以减少 临床相关NASH小鼠模型中的脂肪变性、炎症和纤维化。以前期强势为导向 我们的原型先导化合物对缓解肝纤维化和代谢的有效性的临床前数据 与NASH相关的功能障碍，AIM 1将专注于药物化学努力，以更好地了解 我们先导化合物的构效关系，并鉴定和表征更有效的相关类似物 表现出更好的拮抗剂活性和类似药物的药理特性的化学物质。在《目标2》中我们将 测试和验证我们的先导化合物的有效性以及由此产生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， 这项工作是第一次研究靶向EphB/EPhinB信号转导系统对 纳什的治疗。这项拟议的研究具有非常重要的意义，因为它将促进 纳什新化合物，靶向信号轴，目前不是感兴趣的或最前沿的 生物技术和制药行业。

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.