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

使用 DYRK1A/B 激酶抑制剂治疗肝病

• 批准号: 10696380
• 负责人: Gian Luca Araldi
• 金额: $ 34.92万
• 依托单位: AVANTI BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696380
• 关键词: Adult; Affect; Alzheimer' s Disease; Animal Disease Models; Anti-Inflammatory Agents; Antidiabetic Drugs; Antioxidants; Area; Attention; Biochemical; Biological Availability; Biological Markers; Biological Sciences; Body Weight; COL1A1 gene; Cell Proliferation; Cellular Assay; Cirrhosis; Collaborations; Collagen; Cyclin D1; Cyclodextrins; Cytoprotection; Data; Deposition; Development; Diabetes Mellitus; Diet; Disease Progression; Distress; Dose; Down Syndrome; Drug Exposure; Drug Kinetics; Drug Metabolic Detoxication; Drug Targeting; Eating; Enhancers; Exhibits; Extracellular Matrix; FABP1 gene; FDA approved; Family member; Fatty Acids; Fatty Liver; Fibrosis; Formulation; Foundations; Genes; Glial Fibrillary Acidic Protein; Goals; Half-Life; Health Promotion; Hepatic; Hepatic Stellate Cell; Hepatotoxicity; High Fat Diet; Histologic; Hypertriglyceridemia; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Interferon Type II; Lead; Liver; Liver Fibrosis; Liver diseases; Measures; Mediating; Metabolic Diseases; Modeling; Molecular Target; Mus; NQO1 gene; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oncology; Oral; Organ; Outcome; Oxidation-Reduction; Pancreas; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Phase I Clinical Trials; Phosphorylation; Phosphotransferases; Pioglitazone; Plasma; Population; Primary carcinoma of the liver cells; Production; Proteins; Proxy; Public Health; Reactive Oxygen Species; Regimen; Research; Role; Route; Safety; Small Business Innovation Research Grant; Specificity; Steatohepatitis; Structure of beta Cell of islet; Testing; Therapeutic; Time; Toxic effect; Translational Research; Tyrosine; Tyrosine Phosphorylation; Vascular Endothelial Growth Factors; Vitamin E; Work; animal efficacy; cell growth regulation; chronic liver disease; combat; cytokine; drug mechanism; efficacy testing; end stage liver disease; fibrogenesis; improved; in vitro activity; in vivo; inhibitor; innovation; insight; interest; kinase inhibitor; lipid biosynthesis; liver inflammation; liver injury; liver transplantation; mouse model; nephrotoxicity; nervous system disorder; neuroinflammation; neuronal survival; neuroprotection; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; nuclear factor-erythroid 2; nuclear factors of activated T-cells; pharmacokinetics and pharmacodynamics; pharmacologic; phase 1 study; response; safety study; small molecule inhibitor; therapeutic target; transcription factor; uptake

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.

项目摘要 非酒精性脂肪肝病（NAFLD）是最普遍的慢性肝病。成年人的四分之一 人口在全球范围内遭受NAFLD的困扰。非酒精性脂肪性肝炎（NASH），一种侵略性的NAFLD，可以 肝硬化和肝细胞癌（HCC）的进展，正在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主要结果，细胞外过多 基质沉积，这是由肝星状细胞（HSC）激活引起的。紧急公共卫生需要 为了开发安全有效的药理治疗，以减轻肝炎，纤维化和脂肪性肝炎。 但是，NAFLD没有FDA批准的药物。 该SBIR I期提案旨在评估ABI-171，这是一种具有选择性的新颖化合物 DYRK1A及其亲密的家庭成员Dyrk1b在生化和细胞分析中。 ABI-171展示了药理学 在几种疾病动物模型中具有疗效证据的活性。我们假设其广泛的抗炎和 细胞保护活性与其对阻碍糖尿病的潜在健康促进活动相结合，减少脂肪酸摄取， 抑制胶原蛋白的积累可能有效地打击了NAFLD。 在此阶段I研究中，提出了两个具体目标：在AIM 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AIM 2中，我们将测试ABI-171在 NASH的高脂饮食模型，该模型既可以提供治疗的机理见解及其潜力 研究翻译。这项研究的详细读数将是体重和食物摄入，胰岛素抵抗，肝损伤 生物标志物，包括组织学和生化评估在内的肝病病理，以及基因和蛋白质的表达水平 参与了DYRK1A/1B介导的细胞细胞保护，炎症，脂肪生成和纤维发生的调节。 该应用程序的成功完成将显着提高 我们的选择性dyrk抑制剂在纳什（Nash 详细检查了代谢性疾病的治疗，并完成了移动Abi的发展所需的发展工作 171进入早期临床试验。