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.

项目概要/摘要 由于人数不断增加，非酒精性脂肪性肝炎 (NASH) 影响着 12% 的美国人 患有代谢性疾病，包括非酒精性脂肪肝、肥胖、代谢综合征和糖尿病。 目前，尚无批准治疗 NASH 的药物选择。 Wnt/β-连环蛋白途径和腺苷 单磷酸激活激酶（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 激活已成为一种对抗 NASH 的机制。我们合成并测试了 新型化合物，其中三唑 YW1128 显示出 Wnt/β-连环蛋白抑制的双重活性 AMPK 通过 Axin 稳定机制激活。 YW1128 显示出令人兴奋的抗肝功效 体外和小鼠体内的脂肪变性。基于YW1128的化学结构，我们最近设计并 合成了新的先导化合物YA6060。在保持双重活性的同时，YA6060表现出了非常有前途的 类似药物的特性，特别是针对肝脂肪变性和纤维化的令人兴奋的功效。我们还发现 端锚聚合酶结合蛋白 1（TNKS1bp1 或 TAB182）作为我们先导化合物的结合靶点。这 拟议的研究旨在检验同时抑制 Wnt/β-catenin 通路的假设 并通过用小分子靶向 TAB182 来稳定细胞 Axin 水平来激活 AMPK，是一种新型的 NASH 治疗的治疗策略。为了检验这个假设，我们将首先综合并评估新的 使用涉及新化合物的迭代过程抑制 Wnt/β-连环蛋白信号传导并激活 AMPK 的化合物 类似物设计、合成化学、药物特性的体外评估以及体内药代动力学和 毒性评价。其次，通过进行体外和体内实验，包括配体结合测定， 基因敲除、转基因表达、基因突变、化学抑制或激活以及各种 通过功能测定，我们将确定先导化合物在肝细胞和小鼠中的作用机制。 最后，我们将评估 YA6060 和基于 YA6060 的新型先导化合物的功效，并验证它们的有效性 具有全方位 NASH 适应症的小鼠模型的药理机制。顺利完成 该项目预计将建立具有 Wnt/β-catenin 抑制和双重活性的小分子 通过靶向 TAB182 和 Axin 稳定化来激活 AMPK 是 NASH 发展的有效资源 疗法。这些知识和小分子预计将极大地有益于未来的研究 了解 NASH 发病机制。最终，我们希望通过一流的技术来改变 NASH 患者的护理 药品。