ERRgamma Agonists to Treat Muscular Dystrophy

核受体(NR)超家族由48个转录因子组成 人类，包括类固醇激素、甲状腺激素、亲脂维生素的受体，以及 胆固醇代谢物。大约一半的神经递质被归类为孤儿受体，因为它们 没有很好地表征配体。因此，许多国家没有经过验证的化学工具。 用来探测这些受体在体内的功能。这是一个迫切的需求，因为几乎所有的 已经确定了配体的NRs是开发治疗药物的良好特征的目标 无数的疾病，包括癌症、糖尿病、动脉粥样硬化、炎症和 内分泌/生殖障碍。雌激素相关的孤儿受体被认为与一种 一系列生理过程，包括脂肪和葡萄糖代谢，线粒体功能， 细胞增殖/癌症，骨形成，肌肉纤维类型测定，血管形成， 发炎和耳聋。因此，针对这些受体的合成配体可能在 治疗各种人类疾病，包括肥胖、2型糖尿病和心血管疾病 (动脉粥样硬化)、癌症、骨质疏松症、炎症和耳聋。我们开发了一部小说， 一流的ERRγ激动剂，体内活性有限。在这里，我们描述一下我们的计划 探索ERRγ合成激动剂功能的化学工具的优化 体内受体，以及确定靶向该受体治疗白血病的潜在效用 与骨骼肌功能障碍相关的疾病，尤其是肌营养不良症。

The nuclear receptor (NR) superfamily constitutes a group of 48 transcription factors in humans, which includes the receptors for steroid hormones, thyroid hormone, lipophilic vitamins, and cholesterol metabolites. Approximately half of NRs are classified as orphan receptors since they do not have well characterized ligands. Thus, a large number of NRs have no validated chemical tools to use to probe the function of these receptors in vivo. This is a critical need given that virtually all the NRs that have identified ligands are well-characterized targets for the development of drugs to treat myriad diseases including cancer, diabetes, atherosclerosis, inflammation, and endocrine/reproductive disorders. The estrogen-related orphan receptors have been implicated in a range of physiological processes including lipid and glucose metabolism, mitochondrial function, cellular proliferation/cancer, bone formation, muscle fiber type determination, vascularization, inflammation and deafness. Thus, synthetic ligands targeting these receptors may hold utility in treatment of myriad human disorders including obesity and type 2 diabetes, cardiovascular disease (atherosclerosis), cancer, osteoporosis, inflammation, and deafness. We have developed a novel, first-in-class ERRγ agonist that display limited in vivo activity. Here, we describe our plans for optimization of ERRγ synthetic agonists for use as chemical tools to probe the function of these receptors in vivo as well as to determine potential utility of targeting this receptor for treatment of diseases associated with skeletal muscle dysfunction, in particular muscular dystrophy.