Screening and Development of Small Molecule HDAC11 Inhibitors to Treat Obesity and Diabetes.

治疗肥胖和糖尿病的小分子 HDAC11 抑制剂的筛选和开发。

• 批准号: 10319956
• 负责人: Hening Lin
• 金额: $ 49.52万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319956
• 关键词: ATP Synthesis Pathway; Adipocytes; Adipose tissue; Adult; BRD2 gene; Biological Assay; Body fat; Body mass index; Brown Fat; Chemicals; Chromatin; Chronic Disease; Collection; Coupled; Data; Deacetylase; Development; Diabetes Mellitus; Drug Targeting; Drug usage; Electron Transport; Energy Intake; Energy Metabolism; Enzymes; Family; Fatty acid glycerol esters; Fluorescence; Foundations; Genes; Genetic Polymorphism; HDAC11 gene; High Pressure Liquid Chromatography; Histone Deacetylase; Human; In Vitro; Inner mitochondrial membrane; Innovative Therapy; Investigation; Lead; Libraries; Lipids; Lysine; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Performance; Pharmaceutical Chemistry; Pharmacotherapy; Population; Protein Isoforms; Proteins; Protons; Reader; Regulation; Research; Role; Structure-Activity Relationship; Therapeutic Intervention; Thermogenesis; Triglycerides; United States; Variant; Weight Gain; amidase; bariatric surgery; base; cheminformatics; design; diet and exercise; drug discovery; feeding; glucose tolerance; high throughput screening; improved; inhibitor; interest; long chain fatty acid; member; miniaturize; novel; obesity treatment; prevent; programs; response; screening; small molecule; small molecule therapeutics; symporter; targeted treatment; uncoupling protein 1

PROJECT SUMMARY/ABSTRACT It is estimated that greater than 1/3 of the population of the United States is obese. Obesity is coupled to the development of many chronic diseases, including type 2 diabetes (T2D), which is projected to afflict over half a billion adults worldwide by 2040. Obesity is a consequence of a disparity between energy intake and expenditure, and decreasing obesity requires a reduction in energy intake and/or an increase in energy expenditure. Aside from diet and exercise, therapeutic interventions for obesity include bariatric surgery and the use of drugs that decrease energy intake. There is intense interest in developing alternative pharmacotherapy for obesity based on increasing energy expenditure via activation of brown adipose tissue (BAT), or `beiging' of white adipose tissue (WAT). Our groups have a longstanding interest in the regulation and function of a family of enzymes known as histone deacetylases (HDACs). During the course of our investigations, we discovered that HDAC11 functions as a repressor of the thermogenic gene program in BAT, and prevents beiging of WAT. Furthermore, we found that HDAC11 is not actually a deacetylase, but instead functions as an efficient lysine defatty-acylase. Since HDAC11-deficient mice are healthy, and HDAC11 has a unique catalytic activity compared to other HDAC isoforms, we hypothesize that selective HDAC11 inhibitors will increase energy expenditure and thus provide an innovative therapy for the treatment of obesity and T2D. Three specific aims are designed to discover small molecules that selectively inhibit HDAC11 defatty-acylase activity.

项目摘要/摘要 据估计，美国超过三分之一的人口患有肥胖症。肥胖症与 许多慢性疾病的发展，包括2型糖尿病(T2D)，预计将困扰超过一半的人 到2040年，全球成年人将达到10亿人。肥胖是能量摄入量和摄入量之间差异的结果 支出，减少肥胖需要减少能量摄入和/或增加能量 支出。除了饮食和运动，肥胖的治疗干预包括减肥手术和 减少能量摄入的药物的使用。人们对开发替代方案有着浓厚的兴趣 通过激活棕色脂肪组织增加能量消耗的肥胖症药物治疗 (BAT)，或白色脂肪组织的“浅色”(WAT)。我们的集团对这项规定有着长期的兴趣 以及一种称为组蛋白脱乙酰酶(HDAC)的酶家族的功能。在我们的过程中 研究发现，HDAC11在蝙蝠中作为产热基因程序的阻遏因子， 并防止Wat的褐变。此外，我们发现HDAC11实际上不是一种脱乙酰酶，而是 作为一种高效的赖氨酸脂肪酰化酶。由于HDAC11缺陷小鼠是健康的，而HDAC11 与其他HDAC亚型相比，具有独特的催化活性，我们假设选择性HDAC11 抑制剂将增加能量消耗，从而为肥胖症的治疗提供一种创新的疗法 和T2D。设计了三个特定的目标来发现选择性抑制HDAC11的小分子 脂肪酰基酶活性。

项目成果

ERRing on the Side of a Mature Heart.

站在成熟的心一边会犯错误。

• DOI: 10.1161/circresaha.120.317052
• 发表时间: 2020
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Major,JenniferL;Bagchi,RushitaA;McKinsey,TimothyA
• 通讯作者: McKinsey,TimothyA

Garcinol Is an HDAC11 Inhibitor.

藤黄醇是HDAC11抑制剂。

• DOI: 10.1021/acschembio.0c00719
• 发表时间: 2020-11-20
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Son SI;Su D;Ho TT;Lin H
• 通讯作者: Lin H

The Fibrosis Across Organs Symposium: A Roadmap for Future Research Priorities.

跨器官纤维化研讨会：未来研究重点路线图。

• DOI: 10.1016/j.amjms.2019.02.014
• 发表时间: 2019
• 期刊: The American journal of the medical sciences
• 作者: Roman,Jesse;Barnes,TeresaR;Kervitsky,DollyJ;Cosgrove,GregoryP;Doherty,DennisE;Tager,AndrewM;Richeldi,Luca;White,EricS;Brenner,DavidA;Schnapp,LynnM;Hewitson,TimothyD;Jugdutt,BodhI;McKinsey,TimothyA;Tosi,JohnD;Crane,
• 通讯作者: Crane,

Putting the Heat on Cardiac Fibrosis: Hsp20 Regulates Myocyte-To-Fibroblast Crosstalk.

治疗心脏纤维化：Hsp20 调节心肌细胞与成纤维细胞的串扰。

• DOI: 10.1016/j.jacbts.2019.03.007
• 发表时间: 2019
• 期刊: JACC. Basic to translational science
• 作者: Major,JenniferL;McKinsey,TimothyA
• 通讯作者: McKinsey,TimothyA