Optimal Selective Thyroid Hormone Analogs for Metabolic Syndrome

用于代谢综合征的最佳选择性甲状腺激素类似物

• 批准号: 8045787
• 负责人: Paul Webb
• 金额: $ 292.15万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045787
• 关键词: Address; Affect; Affinity; Animal Model; Animals; Atherosclerosis; Binding; Biological Assay; Biotechnology; Blood Glucose; Body fat; Cardiovascular Diseases; Catabolism; Cell Culture Techniques; Chemistry; Cholesterol; Data; Data Reporting; Death Rate; Development; Diabetic mouse; Disease; Dose; Dyslipidemias; Effectiveness; Epidemic; Exhibits; Fatty Liver; Fatty acid glycerol esters; Future; GC 1 compound; Gene Expression; Generations; Genes; Genomics; Head; Health; Heart Rate; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hormones; Human; In Vitro; Incidence; Insulin Resistance; LDL Cholesterol Lipoproteins; Learning; Life Style; Ligands; Lipids; Lipoprotein (a); Liver; Liver diseases; Low-Density Lipoproteins; Metabolic Diseases; Metabolic syndrome; Metabolism; Mouse Cell Line; Muscle; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Obesity associated disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Play; Primates; Property; Protein Isoforms; Proteins; Public Domains; Research Personnel; Rodent Model; Role; Serum; Staging; Structure; System; Testing; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Triglycerides; United States; Weight; Western World; Work; X-Ray Crystallography; analog; base; bone; chemical property; combat; comparative; hormone analog; improved; innovation; insulin sensitivity; mortality; mouse model; non-alcoholic; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; pre-clinical; preclinical study; prevent; receptor; reverse cholesterol transport; structural biology; success; uptake

DESCRIPTION (provided by applicant): The combined threat of cardiovascular disease (CVD) and obesity is arguably the worst major health problem affecting the western world. While there has been progress in reducing CVD mortality, death rates remain unacceptably high. Current approaches to treatment of obesity and associated diseases such as T2DM have not reduced the epidemics; in spite of aggressive efforts to modify lifestyles in the United States; success will require many years. It is essential to develop innovative treatments for these disorders. Nuclear receptors (NRs) are one of the most important classes of regulatory molecules and major targets for pharmaceuticals. Thyroid hormones (THs) and their cognate nuclear receptors (TRs 1 and 2) are master regulators of metabolism. While TH excess leads to deleterious effects such as elevated heart rate, arrythmias and muscle and bone catabolism there are beneficial effects such as reduced cholesterol and fat loss. Our team successfully developed ways to create selective TR modulators (STRMs) to safely elicit beneficial effects of TH excess states without harmful effects and several biotechnology companies have created compounds based on these principles. The STRMs have shown great promise for treatment of metabolic disease in preclinical animal models, where they variously reverse dyslipidemias, promote reverse cholesterol transport, reduce body fat in rodent models of obesity and primates, reduce liver fat in rodent models of non-alcoholic hepatic steatosis and improve insulin sensitivity in diabetic mice without obvious harmful effects. At least three of these compounds have been in human trials, with very promising results for treatment of high low density lipoprotein (LDL) cholesterol and elevations in other atherogenic serum lipids. We now realize, however, that existing STRMs exhibit distinctive combinations of different modes of selectivity; preferential binding to the TR2-isoform versus TR1, liver and tissue uptake selectivity and gene selectivity. We do not know which STRM is best for particular indications, what combination of selective effects is most desirable and whether the same or different combinations of selective actions are needed to treat different aspects of CVD and metabolic disorders. It is often hard to compare different compounds because data has not entered the public domain. In this study, we will define actions of existing STRMs and novel concept compounds and understand which aspects of their actions and properties will be most useful for different aspects of metabolic disease. Our strategy is to perform head to head comparisons of the existing and recently discovered ligands with distinct selectivity profiles and detailed analysis of mechanism in vitro, in cell culture and in well chosen mouse models of metabolic disease. Results will help fast-track the best of a potentially very useful group of compounds into tests in late-stage pre- clinical animal models and human trials and will help us define the best combination of selective actions for 2nd generation compounds. PUBLIC HEALTH RELEVANCE: Proteins called nuclear receptors play important roles in every major disease that affects the western world and many successful drugs already work through these proteins. We will find drugs that will safely treat high cholesterol and obesity and work through one class of these proteins, thyroid hormone receptors.

描述（由申请人提供）：心血管疾病（CVD）和肥胖的联合威胁可以说是影响西方世界的最严重的主要健康问题。虽然在降低心血管疾病死亡率方面取得了进展，但死亡率仍然高得令人无法接受。目前治疗肥胖症和相关疾病（如T2 DM）的方法并没有减少流行病;尽管美国积极努力改变生活方式;但成功将需要许多年。必须为这些疾病开发创新的治疗方法。核受体是一类重要的调控分子，也是药物的主要靶点。甲状腺激素（TH）及其同源核受体（TRs 1和2）是代谢的主要调节因子。虽然TH过量导致有害作用，如心率升高，心律失常和肌肉和骨钙素，但也有有益的作用，如降低胆固醇和脂肪损失。我们的团队成功地开发了创造选择性TR调节剂（STRM）的方法，以安全地引发TH过量状态的有益效果，而不会产生有害影响，几家生物技术公司已经根据这些原则创造了化合物。STRM在临床前动物模型中已经显示出治疗代谢疾病的巨大前景，其中它们以各种方式逆转血脂异常，促进胆固醇逆向转运，减少肥胖啮齿动物模型和灵长类动物中的体脂，减少非酒精性肝脂肪变性啮齿动物模型中的肝脏脂肪，并改善糖尿病小鼠中的胰岛素敏感性，而没有明显的有害作用。这些化合物中至少有三种已经在人体试验中，对于治疗高低密度脂蛋白（LDL）胆固醇和其他致动脉粥样硬化血清脂质升高具有非常有希望的结果。然而，我们现在意识到，现有的STRM表现出不同模式的选择性的独特组合;优先结合TR 2-亚型而不是TR 1，肝脏和组织摄取选择性和基因选择性。我们不知道哪种STRM最适合特定的适应症，什么样的选择性作用组合是最理想的，以及是否需要相同或不同的选择性作用组合来治疗CVD和代谢紊乱的不同方面。通常很难比较不同的化合物，因为数据还没有进入公共领域。在这项研究中，我们将定义现有的STRM和新概念化合物的作用，并了解它们的作用和性质的哪些方面对代谢疾病的不同方面最有用。我们的策略是对现有的和最近发现的具有不同选择性的配体进行头对头比较，并在体外、细胞培养和精心选择的代谢疾病小鼠模型中详细分析其机制。结果将有助于快速跟踪一组潜在的非常有用的化合物中的最佳化合物，以进行后期临床前动物模型和人体试验的测试，并将帮助我们确定第二代化合物选择性作用的最佳组合。 公共卫生相关性：被称为核受体的蛋白质在影响西方世界的每一种主要疾病中起着重要作用，许多成功的药物已经通过这些蛋白质起作用。我们将找到安全治疗高胆固醇和肥胖的药物，并通过一类蛋白质，甲状腺激素受体起作用。

项目成果

Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver.

• DOI: 10.1530/joe-14-0440
• 发表时间: 2015-03
• 期刊: The Journal of endocrinology
• 作者: Aijun Zhang;D. Sieglaff;J. P. York;J. Suh;S. Ayers;Glenn E. Winnier;A. Kharitonenkov;C. Pin;Pumin Zhang;P. Webb;Xuefeng Xia

Thyroid hormone induction of human cholesterol 7 alpha-hydroxylase (Cyp7a1) in vitro.

• DOI: 10.1016/j.mce.2014.02.003
• 发表时间: 2014-05-05
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Lammel Lindemann JA;Angajala A;Engler DA;Webb P;Ayers SD
• 通讯作者: Ayers SD

A thyroid hormone receptor/KLF9 axis in human hepatocytes and pluripotent stem cells.

• DOI: 10.1002/stem.1875
• 发表时间: 2015-03
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Cvoro A;Devito L;Milton FA;Noli L;Zhang A;Filippi C;Sakai K;Suh JH;H Sieglaff D;Dhawan A;Sakai T;Ilic D;Webb P
• 通讯作者: Webb P

Genome-wide binding patterns of thyroid hormone receptor beta.

• DOI: 10.1371/journal.pone.0081186
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ayers S;Switnicki MP;Angajala A;Lammel J;Arumanayagam AS;Webb P
• 通讯作者: Webb P

Opening the black box: revealing the molecular basis of thyroid hormone transport.

打开黑匣子：揭示甲状腺激素转运的分子基础。

• DOI: 10.1210/en.2013-1393
• 发表时间: 2013
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Martagón,AlexandroJ;Philips,KevinJ;Webb,Paul
• 通讯作者: Webb,Paul