Optimization of ERRg-specific ligands as in vivo Chemical Probes

作为体内化学探针的 ERRg 特异性配体的优化

• 批准号: 9382901
• 负责人: Patrick Robert Griffin
• 金额: $ 39.84万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-17 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9382901
• 关键词: 4-Hydroxy-Tamoxifen; Agonist; Animal Disease Models; Animals; Binding Proteins; Biological Assay; Birth; Blood Vessels; Brain; Cardiovascular Diseases; Cell Line; Cell Respiration; Chemicals; Complement; Crystallography; Data; Development; Diet; Diethylstilbestrol; Disease; Disease model; Drug Kinetics; Drug or chemical Tissue Distribution; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Exhibits; Exposure to; Functional disorder; Funding Mechanisms; Gene Targeting; Genetically Engineered Mouse; Goals; Grant; Heart; Heart Abnormalities; Human; Hyperglycemia; In Vitro; Kidney; Letters; Ligand Binding; Ligands; Metabolic; Metabolic dysfunction; Microsomes; Mitochondria; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle function; Muscular Atrophy; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Orphan Receptor; Nuclear Receptors; Obesity; Oxygen Consumption; Pharmacodynamics; Pharmacology; Phenotype; Physiological; Physiological Processes; Plasma Proteins; Property; Reporter; Reporting; Repression; Research; Resistance; Role; Skeletal Muscle; Solubility; Source; Spinal Cord; Stress; Therapeutic; Tissues; Validation; Weight Gain; age related; db/db mouse; design; drug candidate; efficacy study; estrogen-related receptor; exercise capacity; glucose metabolism; hepatic gluconeogenesis; human disease; improved; in vitro Assay; in vivo; in vivo Model; in vivo evaluation; insight; interest; lead series; lipid metabolism; muscle aging; novel; overexpression; preclinical development; promoter; public health relevance; receptor; receptor function; response; small molecule; therapeutic development; tool; transcription factor; treadmill

 DESCRIPTION (provided by applicant): The nuclear receptor (NR) superfamily of ligand regulated transcription factors has proven to be a rich source of targets for the development of therapeutics for a wide range of human diseases. The estrogen-related receptors (ERRα , ERRβ and ERRγ) regulate several physiological processes, including mitochondrial function, glucose and lipid metabolism, and muscle fiber type determination. While structurally related to the estrogen receptors ERα and ERβ, they do not bind endogenous ER ligands. The ERR's are constitutively active orphan nuclear receptors, and while ERRα and ERRβ are more ubiquitously expressed, ERRγ it is more restricted to metabolically active and highly vascularized tissues such as heart, kidney, brain and skeletal muscles. ERRγ-/- mice fail to thrive shortly after birth due to abnormal heart and spinal cord development, but haploinsufficient ERRγ+/- mice are viable and phenotypically normal in the absence of stress. ERRγ+/- mice exhibit decreased exercise capacity and muscle mitochondrial function compared to their WT littermates. In mice, muscle-specific forced expression of ERRγ increased oxygen consumption, treadmill endurance, mitochondrial function and these animals were resistant to diet-induced weight gain. Interestingly, repression of ERRγ expression in db/db mice ameliorated hyperglycemia via inhibition of hepatic gluconeogenesis. Given the receptors specific tissue distribution and important physiological functions, the identification of ERRγ-selective small molecule modulators would be valuable chemical probes and pharmacological tools. Our goal is to optimize our current lead series of ERRγ ligands with the appropriate potency, selectivity and pharmacokinetic (PK) properties to provide ERRγ probes to interrogate the function of the receptor in vivo and its role in the pathophysiology of disease. In order to achieve this goal, we propose the following Specific Aims: 1) Further develop and optimize ERRγ-selective ligands with improved potency, selectivity and pharmacokinetic properties; 2) Characterize the pharmacology of these ERRγ-selective compounds in vitro and in vivo. Accomplishment of these Aims will provide novel, first-in-class ligands that selectively modulate ERRγ activity. These probes will be useful for the study of the receptors function in vivo in animal models of disease such as obesity and type-2 diabetes, cardiovascular disease and muscle atrophy.

 描述（由申请人提供）：配体调节转录因子的核受体（NR）超家族已被证明是开发多种人类疾病疗法的丰富靶标来源。雌激素相关受体（ERRα、ERRβ 和 ERRγ）调节多种生理过程，包括线粒体功能、葡萄糖和脂质代谢以及肌纤维类型确定。虽然在结构上与雌激素受体 ERα 和 ERβ 相关，但它们不结合内源性 ER 配体。 ERR 是组成型活性孤儿核受体，虽然 ERRα 和 ERRβ 表达更为普遍，但 ERRγ 更局限于代谢活跃和高度血管化的组织，例如心脏、肾脏、大脑和骨骼肌。 ERRγ-/- 小鼠出生后不久就无法茁壮成长 由于心脏和脊髓发育异常，但单倍体不足的 ERRγ+/- 小鼠在没有应激的情况下仍能存活且表型正常。与 WT 同窝小鼠相比，ERRγ+/- 小鼠表现出运动能力和肌肉线粒体功能下降。在小鼠中，ERRγ 的肌肉特异性强制表达增加了耗氧量、跑步机耐力和线粒体功能，并且这些动物对饮食引起的体重增加具有抵抗力。有趣的是，抑制 db/db 小鼠中的 ERRγ 表达可通过抑制肝糖异生来改善高血糖。鉴于受体的特定组织分布和重要的生理功能，ERRγ选择性小分子调节剂的鉴定将是有价值的化学探针和药理学工具。我们的目标是优化我们目前领先的 ERRγ 配体系列，使其具有适当的效力、选择性和药代动力学 (PK) 特性，以提供 ERRγ 探针来探究受体的体内功能及其在疾病病理生理学中的作用。为了实现这一目标，我们提出以下具体目标： 1）进一步开发和优化具有改进效力、选择性和药代动力学特性的ERRγ选择性配体； 2) 表征这些 ERRγ 选择性化合物的体外和体内药理学。这些目标的实现将提供选择性调节 ERRγ 活性的新型一流配体。这些探针将有助于研究肥胖和2型糖尿病、心血管疾病和肌肉萎缩等疾病动物模型中受体的体内功能。