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

基本信息

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
项目类别：
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

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

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项目摘要

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/摘要由于个体越来越多的人，非酒精性脂肪性肝炎（NASH）影响了12％的美国人具有代谢性疾病，包括非酒精性脂肪肝疾病，肥胖，代谢综合征和糖尿病。目前，尚未批准NASH的药品选项。 Wnt/β-catenin途径和腺苷单磷酸激活的激酶（AMPK）是调节肝代谢的关键途径。遗传和药理学证据通过抑制Wnt/β-catenin对肝素代谢的益处支持。同时，AMPK激活已成为反对NASH的机制。我们已经合成并测试了新颖的化合物类别，其中三唑YW1128显示了Wnt/β-catenin抑制的双重活性 AMPK通过轴稳定机制激活。 YW1128对肝脏表现出令人兴奋的效率体外和小鼠的脂肪变性。根据YW1128的化学结构，我们最近设计了合成了新的铅YA6060。在维护双重活动的同时，YA6060公开了一个巨大的承诺类似药物的特征，尤其是针对肝脂肪变性和纤维化的令人兴奋的效率。我们也发现了坦克酸盐酶结合蛋白1（TNKS1BP1或TAB182）是我们铅化合物的结合靶标。这拟议的研究旨在测试仅抑制Wnt/beta-catenin途径的假设通过用小分子靶向TAB182稳定细胞轴的激活AMPK是一种新型 NASH治疗的治疗策略。为了检验这一假设，我们将首先合成并评估新的使用涉及新的迭代过程，可抑制Wnt/β-catenin信号传导和激活AMPK的化合物模拟设计，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估。其次，通过进行体外和体内实验，包括配体结合测定，遗传敲低，转化表达，遗传突变，化学抑制或激活以及各种功能分析，我们将确定肝细胞和小鼠中铅化合物的作用机理。最后，我们将评估YA6060的效率和新的基于YA6060的铅化合物并验证其具有各种纳什指示的小鼠模型中的药理机制。成功完成预计该项目将确定具有Wnt/beta-catenin抑制双重活性的小分子和通过靶向TAB182和AXIN稳定化的AMPK激活是开发NASH的有效资源治疗。预计知识和小分子将极大地有益于未来的研究了解纳什发病机理。最终，我们希望通过一流的纳什患者护理改变纳什的患者护理药品。