USE OF DYRK1A/B KINASE INHIBITORS FOR THE TREATMENT OF LIVER DISEASES

项目总结 非酒精性脂肪性肝病(NAFLD)是最常见的慢性肝病。四分之一的成年人 全世界的人都患有非酒精性脂肪肝。非酒精性脂肪性肝炎(NASH)是NAFLD的侵袭性形式，可以 进展为肝硬变和肝细胞癌，并迅速成为终末期肝病的主要原因 和肝移植。肝纤维化是慢性肝病的一个主要后果，在慢性肝病中细胞外过量 基质沉积，这是由肝星状细胞(HSCs)激活引起的。有一种迫切的公共卫生需求 开发安全有效的药物治疗，以减轻肝脏炎症、纤维化和脂肪性肝炎。 然而，目前还没有FDA批准的治疗NAFLD的药物。 这项SBIR第一阶段提案旨在评估ABI-171，一种具有良好选择性的新型化合物 DYRK1A及其近亲家族成员DYRK1B在生化和细胞分析中的应用。ABI-171展示药理作用 在几种疾病动物模型中有疗效的证据的活性。我们假设它广泛的抗炎和 细胞保护活性与其潜在的促进健康的活性相结合，可抑制糖尿病，减少脂肪酸摄取， 抑制胶原蛋白堆积可有效对抗NAFLD。 在这一阶段的研究中，提出了两个具体目标：在目标1中，我们将评估ABI-171在 感兴趣的器官，即肝脏，以提高其安全性。在目标2中，我们将测试ABI-171在 NASH的高脂肪饮食模型，该模型为治疗及其潜在的治疗提供了良好的机制洞察力 研究翻译。这项研究的详细读数将包括体重和食物摄入量、胰岛素抵抗、肝脏损伤 生物标志物、肝脏病理学，包括组织学和生化评估，以及基因和蛋白质的表达水平 参与DYRK1A/1B介导的细胞保护、炎症、脂肪生成和纤维化的调节。 这项申请的成功完成将极大地提高药物的疗效和作用机制 我们在NASH中的选择性Dyrk抑制剂，从而为药物活性将被 更详细地检查代谢紊乱的治疗，并完成移动ABI所需的开发工作- 171进入早期临床试验。

PROJECT SUMMARY Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. One-fourth of the adult population suffers from NAFLD worldwide. Nonalcoholic steatohepatitis (NASH), the aggressive form of NAFLD, can progress to cirrhosis and hepatocellular cancer (HCC) and is rapidly becoming the leading cause of end-stage liver disease and liver transplantation. Liver fibrosis is a major consequence of chronic liver disease, where the excess extracellular matrix is deposited, which is caused by the activation of hepatic stellate cells (HSCs). There is an urgent public health need to develop safe and effective pharmacological treatments to alleviate hepatic inflammation, fibrosis, and steatohepatitis. However, there are no FDA-approved medications for NAFLD. This SBIR Phase I proposal seeks to evaluate ABI-171, a novel compound with demonstrated selectivity for DYRK1A and its close family member DYRK1B in biochemical and cellular assays. ABI-171 exhibits pharmacological activity with evidence of efficacy in several animal models of disease. We hypothesize that its broad anti-inflammatory and cytoprotective activities combined with its potential health-promoting activities to thwart diabetes, reduce fatty acid uptake, and suppress collagen accumulation may effectively combat NAFLD. In this Phase I study, two specific aims are proposed: in Aim 1 we will evaluate the accumulation of ABI-171 in the organs of interest, namely the liver, to advance its safety profile. In Aim 2, we will test the efficacy of ABI-171 in the high-fat diet model of NASH, which is well-established for providing mechanistic insight of treatments and its potential for research translation. Detailed readouts for this study will be bodyweight and food intake, insulin resistance, liver injury biomarkers, liver pathology including histological and biochemical assessments, and expression levels of genes and proteins involved in DYRK1A/1B-mediated regulation of cellular cytoprotection, inflammation, lipogenesis, and fibrogenesis. The successful completion of this application will significantly advance the efficacy and mechanism of action of our selective DYRK inhibitor in NASH, thus forming strong foundation for a Phase 2 project in which drug activity will be examined in more detail for the treatment of metabolic disorders and complete the development work needed to move ABI- 171 into an early-stage clinical trial.