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

项目概要/摘要 据估计，超过1/3的美国人口肥胖。肥胖与 许多慢性疾病的发展，包括2型糖尿病（T2 D），预计将影响超过一半的人。 到2040年，全球将有10亿成年人。肥胖症是能量摄入量和体重之间不平衡的结果。 减少肥胖需要减少能量摄入和/或增加能量消耗。 支出除了饮食和锻炼，肥胖症的治疗干预包括减肥手术， 使用减少能量摄入的药物。人们对开发替代能源有着浓厚的兴趣 基于通过激活棕色脂肪组织增加能量消耗的肥胖症药物疗法 (BAT)或白色脂肪组织（WAT）的“beiging”。我们的团体对监管有着长期的兴趣 和称为组蛋白脱乙酰酶（HDAC）的酶家族的功能。在我们的 调查中，我们发现HDAC 11作为BAT中产热基因程序的抑制子， 并防止WAT的褐变。此外，我们发现HDAC 11实际上不是脱乙酰酶，而是 作为一种有效的赖氨酸脱酰酶发挥作用。由于HDAC 11缺陷小鼠是健康的，并且HDAC 11具有 与其他HDAC亚型相比，HDAC 11具有独特的催化活性，我们假设选择性HDAC 11 抑制剂将增加能量消耗，从而为治疗肥胖提供创新疗法 和T2 D。三个特定的目标旨在发现选择性抑制HDAC 11的小分子 脱脂酰化酶活性。

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.