Axin Stabilization by Novel Small Molecules to Treat Non-alcoholic Steatohepatitis

新型小分子稳定轴蛋白治疗非酒精性脂肪性肝炎

• 批准号: 10659312
• 负责人: Yan Shu
• 金额: $ 53.9万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659312
• 关键词: Address; Adenosine Monophosphate; Adherence; Affect; American; Animal Model; Attention; Azoles; Benign; Biguanides; Binding; Binding Proteins; Biological Assay; Biotinylation; Cells; Chemical Structure; Chemicals; Cicatrix; Clinical; DNA Sequence Alteration; Diabetes Mellitus; Down-Regulation; Drug Kinetics; Drug or chemical Tissue Distribution; Evaluation; Exhibits; Fatty Liver; Fibrosis; Generations; Genetic; Goals; Hepatic; Hepatocyte; Hybrids; In Vitro; Incidence; Individual; Knowledge; Lead; Life Style; Ligand Binding; Liver; Liver Fibrosis; Medical; Metabolic; Metabolic Diseases; Metabolic syndrome; Molecular Mechanisms of Action; Mus; Obesity; Organic Cation Transporter 1; Outcomes Research; Overnutrition; Pathogenesis; Pathway interactions; Patient Care; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phosphotransferases; Play; Population; Process; Property; Proteomics; Regulation; Research; Resource Development; Role; Safety; Signal Transduction; Swelling; Synthesis Chemistry; Tankyrase; Testing; Therapeutic; Toxic effect; Wettability; analog; beta catenin; design; diet and exercise; dietary control; drinking water; drug candidate; drug development; drug discovery; efficacy evaluation; experimental study; functional decline; genetic manipulation; in vivo; innovation; knock-down; lead optimization; liver metabolism; liver transplantation; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; sensor; small molecule; success; sugar; therapeutically effective; transgene expression; western diet

PROJECT SUMMARY/ABSTRACT Non-alcoholic steatohepatitis (NASH) affects 12% of Americans due to the growing number of individuals with metabolic disorders, including nonalcoholic fatty liver disease, obesity, metabolic syndromes, and diabetes. At present, there are no pharmacological options approved for NASH. Wnt/beta-catenin pathway and adenosine monophosphate-activated kinase (AMPK) are crucial pathways in regulation of hepatic metabolism. Genetic and pharmacological evidence supports a benefit by inhibition of Wnt/beta-catenin on hepatic metabolism; meanwhile, AMPK activation has emerged as a mechanism against NASH. We have synthesized and tested a novel class of compounds, of which triazole YW1128 showed dual activities of Wnt/beta-catenin inhibition and AMPK activation via the mechanism of Axin stabilization. YW1128 showed an exciting efficacy against hepatic steatosis both in vitro and in mice. Based on the chemical structure of YW1128, we recently designed and synthesized the new lead YA6060. While maintaining the dual activities, YA6060 has exhibited a highly promising drug-like profile and particularly an exciting efficacy against hepatic steatosis and fibrosis. We also discovered the tankyrase-binding protein 1 (TNKS1bp1 or TAB182) as a binding target of our lead compounds. The proposed studies are intended to test the hypothesis that simultaneously inhibiting Wnt/beta-catenin pathway and activating AMPK, by stabilizing cellular Axin level via targeting TAB182 with small molecules, is a novel therapeutic strategy for NASH treatment. To test this hypothesis, we will first synthesize and evaluate new compounds that inhibit Wnt/β-catenin signaling and activate AMPK, using an iterative process involving new analog design, synthetic chemistry, in vitro assessment of drug properties, and in vivo pharmacokinetic and toxicity evaluation. Second, by conducting in vitro and in vivo experiments including ligand binding assays, genetic knockdown, transgene expression, genetic mutation, chemical inhibition or activation, and various functional assays, we will determine the mechanism of action for lead compounds in hepatocytes and mice. Lastly, we will evaluate the efficacy of YA6060 and a new YA6060-based lead compound and validate their pharmacological mechanism in mouse models with a full range of NASH indications. Successful completion of this project is expected to establish that small molecules with dual activities of Wnt/beta-catenin inhibition and AMPK activation via targeting TAB182 and Axin stabilization is a valid resource for the development of NASH therapeutics. The knowledge and small molecules are expected to greatly benefit future research in understanding of NASH pathogenesis. Eventually, we expect to transform NASH patient care with a first-in-class drug.

项目摘要/摘要 非酒精性脂肪性肝炎(NASH)影响了12%的美国人，因为越来越多的人 代谢紊乱，包括非酒精性脂肪肝、肥胖、代谢综合征和糖尿病。 目前，还没有批准用于NASH的药物选择。WNT/β-连环蛋白途径与腺苷 单磷酸激活的激酶(AMPK)是调节肝脏代谢的重要途径。遗传和 药理学证据支持抑制Wnt/β-catenin对肝脏代谢的益处； 与此同时，AMPK的激活已经成为对抗NASH的一种机制。我们已经合成并测试了一种 一类新化合物，其中三氮唑YW1128具有Wnt/β-连环蛋白抑制和β-连环蛋白双重活性 通过轴蛋白稳定机制激活AMPK。YW1128显示出令人兴奋的抗肝作用 在体外和小鼠体内都有脂肪变性。根据YW1128的化学结构，我们最近设计和 合成了新的铅YA6060。在保持双重活性的同时，YA6060表现出了极具前景的 类似药物的特征，特别是对肝脏脂肪变性和纤维化具有令人兴奋的疗效。我们还发现 Tankyrase结合蛋白1(TNKS1bp1或TAB182)作为我们的先导化合物的结合靶标。这个 拟议的研究旨在验证同时抑制Wnt/β-连环蛋白途径的假设 而通过用小分子靶向TAB182来稳定细胞轴蛋白水平来激活AMPK是一种新的方法 NASH治疗的治疗策略。为了验证这一假设，我们将首先综合和评估新的 抑制Wnt/β-连环蛋白信号转导并激活AMPK的化合物，使用的迭代过程涉及新的 模拟设计、合成化学、药物性质的体外评估以及体内药代动力学和 毒性评价。第二，通过进行包括配体结合分析在内的体外和体内实验， 基因敲除、转基因表达、基因突变、化学抑制或激活，以及各种 通过功能分析，我们将确定铅化合物在肝细胞和小鼠中的作用机制。 最后，我们将评估YA6060和一种新的基于YA6060的铅化合物的有效性，并验证它们的有效性 具有全系列NASH指征的小鼠模型的药理机制。成功完成 该项目有望建立具有Wnt/β-连环蛋白抑制和β-连环蛋白双重活性的小分子 通过靶向TAB182和Axin稳定激活AMPK是发展NASH的有效资源 治疗学。这些知识和小分子有望极大地促进未来的研究 对NASH发病机制的认识。最终，我们希望以一流的方式改变NASH患者的护理 毒品。