Them1 Inhibitors for the Management of Non-Alcoholic Fatty Liver Disease

Them1 治疗非酒精性脂肪肝的抑制剂

• 批准号: 10666090
• 负责人: DAVID E. COHEN
• 金额: $ 50万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666090
• 关键词: Acyl Coenzyme A; Address; Adipocytes; Adipose tissue; Biological; Biological Assay; Biophysics; Brown Fat; Calories; Cell Culture Techniques; Cells; Consumption; Coupled; Data; Development; Disease; Dose; Drug Kinetics; Energy Metabolism; Enzymatic Biochemistry; Enzymes; Fatty Acids; Fatty Liver; Genes; Goals; Hepatic; Hepatocyte; Homeostasis; Human; In Vitro; Inflammation; Inflammation Mediators; Intervention; Lead; Left; Lipid Binding; Lipids; Liver; Mediating; Medical; Medication Management; Metabolic; Mission; Mitochondria; Modality; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome Study; Overnutrition; Pathogenesis; Pathogenicity; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Positioning Attribute; Prevalence; Production; Property; Public Health; Regulation; Research; Resistance; Role; Route; Safety; Schedule; Specificity; Structure; Structure-Activity Relationship; Testing; Therapeutic; Thermogenesis; Tissues; Triglycerides; Validation; cytotoxicity; design; drug-like compound; efficacy testing; experimental study; fatty acid metabolism; fatty acid oxidation; glucose metabolism; glucose production; high throughput screening; improved; in vivo evaluation; inhibitor; lead optimization; member; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; nutrient metabolism; obesity management; parent grant; pharmacologic; pre-clinical; prevent; small molecule; small molecule inhibitor; structural determinants; therapeutic lead compound

PROJECT SUMMARY/ABSTRACT There is a critical need for effective pharmacotherapy for the management of non-alcoholic fatty liver disease (NAFLD). The proposed research is to conduct early-stage preclinical validation of new therapeutic leads that target thioesterase superfamily member 1 (Them1; synonym Acyl-CoA thioesterase 11), a key enzyme of fatty acid metabolism that becomes maladaptive in NAFLD. The long-term goal is to develop inhibitors of Them1 as a therapeutic modality in the management of human NAFLD. The objective of this research is to optimize the drug-like properties of small molecule inhibitors in order to create lead compounds, and to demonstrate their safety, efficacy and specificity in cell-based assays and in experimental NAFLD using mice. Targeting Them1 with optimized small molecule inhibitors is expected to mitigate NAFLD by: 1) Increasing energy expenditure in thermogenic brown and beige adipose tissue; 2) Decreasing hepatic steatosis, as well as glucose production by the liver; and 3) Reducing inflammation in white adipose tissue. The rationale is that a lead compound that addresses these three independent pathogenic contributions of Them1 should prove effective in NAFLD. We have completed a high-throughput small molecule screen that has identified promising inhibitors targeting the fatty acyl-CoA thioesterase activity of Them1. Motivated by extensive mechanistic data on the contributions of Them1 to NAFLD pathogenesis, the development of inhibitors into lead compounds will be accomplished in three specific aims: 1) To optimize the potency and specificity of Them1 small molecule inhibitors; 2) To establish drug-like properties and efficacy in cell culture of early lead compounds; and 3) To evaluate therapeutic lead compounds in experimental NAFLD using mice. In Aim 1, small molecule inhibitors will be optimized by medicinal chemistry strategies to improve potency, specificity and drug-like properties. These efforts will be guided by structure-activity relationships based on in vitro enzymatic assays, as well as biophysical and structural determinants of Them1-inhibitor interactions. Aim 2 will evaluate early lead compounds for drug-like properties, as well as cytotoxicity. Selected early leads will then be tested for efficacy in primary cultured mouse and human cells for their capacities to increase fatty acid oxidation in brown adipocytes and hepatocytes, to reduce hepatic glucose production in hepatocytes and to decrease production of inflammatory mediators by white adipocytes. Specificity will be assessed using cells cultured from Them1-/- mice. In Aim 3, lead compounds will be tested in mice for pharmacokinetics and tolerability. Upon establishing dosing routes and schedules, efficacy to prevent and to reverse NAFLD will be assessed in mouse models. Off-target effects will be evaluated using Them1-/- mice. The expected outcome of these studies is the development and pre-clinical validation of optimized lead Them1 inhibitors that leverage novel mechanisms of energy homeostasis, fatty acid and glucose metabolism, as well as inflammation in the medical management of NAFLD.

项目总结/摘要 目前迫切需要有效的药物治疗来治疗非酒精性脂肪肝 （NAFLD）。拟议的研究是对新的治疗药物进行早期临床前验证， 靶向硫酯酶超家族成员1（Them 1;同义词酰基-CoA硫酯酶11），脂肪酸合成关键酶 酸代谢在NAFLD中变得不适应。长期目标是开发Them 1的抑制剂， 在人类NAFLD管理中的治疗方式。本研究的目的是优化 小分子抑制剂的类药物性质，以创建先导化合物，并证明其 在基于细胞的测定和使用小鼠的实验性NAFLD中的安全性、有效性和特异性。目标主题1 使用优化的小分子抑制剂，预期通过以下方式减轻NAFLD：1）增加能量消耗， 产热棕色和米色脂肪组织; 2）减少肝脏脂肪变性以及葡萄糖生成 通过肝脏;和3）减少白色脂肪组织的炎症。其理由是，一种铅化合物， 解决了Them 1的这三个独立的致病作用，应该证明在NAFLD中有效。我们 已经完成了一项高通量的小分子筛选，已经确定了有希望的抑制剂靶向 Them 1的脂肪酰基-CoA硫酯酶活性。受到关于以下因素的贡献的大量机械数据的启发， Them 1对NAFLD发病机制的研究，将抑制剂开发成先导化合物将在 三个具体目标：1）优化Them 1小分子抑制剂的效力和特异性; 2） 建立早期先导化合物在细胞培养中的药物样性质和功效;和3）评价 使用小鼠进行的实验性NAFLD中的治疗性先导化合物。在目标1中，小分子抑制剂将是 通过药物化学策略进行优化，以提高效力、特异性和药物样性质。这些 这些努力将以基于体外酶测定的结构-活性关系为指导， Them 1-抑制剂相互作用的生物物理和结构决定因素。目标2将评价早期电极导线 化合物的药物样性质，以及细胞毒性。然后将对选定的早期导联进行疗效测试 在原代培养的小鼠和人类细胞中， 脂肪细胞和肝细胞，以减少肝细胞中的肝葡萄糖产生， 白色脂肪细胞释放炎症介质。将使用Them 1-/-培养的细胞评估特异性 小鼠在目标3中，将在小鼠中测试先导化合物的药代动力学和耐受性。一旦建立 将在小鼠模型中评估给药途径和时间表、预防和逆转NAFLD的功效。 将使用Them 1-/-小鼠评价脱靶效应。这些研究的预期结果是， 开发和临床前验证优化的先导Them 1抑制剂， 能量稳态、脂肪酸和葡萄糖代谢以及炎症在医疗管理中的作用 的NAFLD。