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NAFLD。非酒精性脂肪性肝炎（NASH）是NAFLD的侵袭性形式， 进展为肝硬化和肝细胞癌（HCC），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主要后果，其中过量的细胞外基质是肝纤维化的主要原因。 基质沉积，这是由肝星状细胞（HSC）活化引起的。公共卫生迫切需要 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，没有FDA批准的NAFLD药物。 该SBIR I期提案旨在评估ABI-171，这是一种新型化合物，对 DYRK 1A及其近缘家族成员DYRK 1B在生物化学和细胞测定中的应用。ABI-171具有药理学活性， 在几种动物疾病模型中具有有效性证据的活性。我们假设其广泛的抗炎和 细胞保护活性与其潜在的健康促进活性相结合，以阻止糖尿病，减少脂肪酸摄取， 和抑制胶原蛋白积累可以有效地对抗NAFLD。 在这项I期研究中，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，其已被充分确立用于提供治疗的机制见解及其治疗的潜力。 研究翻译这项研究的详细读数将是体重和食物摄入量、胰岛素抵抗、肝损伤 生物标志物、肝脏病理学（包括组织学和生物化学评估）以及基因和蛋白质的表达水平 参与DYRK 1A/1B介导的细胞保护、炎症、脂肪生成和纤维生成的调节。 该申请的成功完成将显著提高 我们在NASH中的选择性DYRK抑制剂，从而为2期项目奠定了坚实的基础，其中药物活性将 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人进入早期临床试验