Towards the discovery of Nurr1-RXR modulators

核受体转录因子Nurr1对调节和维持几个 哺乳动物大脑发育和动态平衡的重要方面。Nurr1调节一个基因程序， 控制对运动神经元功能至关重要的多巴胺能神经元的发育和功能 以及控制帕金森氏症患者退化的运动。此外，最近的研究 研究表明Nurr1是调节神经炎症和淀粉样β蛋白积聚的重要因子 (Aβ)发生在阿尔茨海默病患者的发病机制中。这些研究和其他研究表明， Nurr1分子激活作为阿尔茨海默病、帕金森病、 以及其他与衰老相关的神经退行性和痴呆性疾病，其特征是神经元丢失 功能。然而，筛选活动发现Nurr1结合和/或转录激活小分子 分子已经产生了有限的Nurr1特异性的复合支架，并且还没有提供有效的，高的 亲和力Nurr1特异性配体。另一种调节Nurr1活动的方法已经获得了势头，即 通过与RXR LBD结合的小分子配体靶向Nurr1-RXR异二聚体复合体。在这 项目，我们将建立在我们强大的初步数据基础上，并开发生物化学和细胞分析，以检测 配体诱导的Nurr1-RXR活性变化。我们研究的成功成果将为我们提供一个平台 筛选、发现和鉴定可作为化学工具研究的Nurr1-RXR选择性配体 阿尔茨海默病、帕金森病和其他与衰老相关的模型中Nurr1-RXR的调节 神经退行性疾病和痴呆症。

The nuclear receptor transcription factor Nurr1 is essential for the regulation and maintenance of several important aspects of mammalian brain development and homeostasis. Nurr1 regulates a gene program that controls the development and function of dopaminergic neurons, which are critical for motor neuron function and control of movement that degenerates in patients with Parkinson’s disease. Furthermore, recent studies show that Nurr1 is an important factor in regulation of neuroinflammation and the accumulation of Amyloid beta (Aβ) that occurs in the pathogenesis of Alzheimer’s disease patients. These and other studies implicate small molecule activation of Nurr1 as a potential therapeutic strategy in Alzheimer’s disease, Parkinson’s disease, and other aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function. However, screening campaigns to discover Nurr1 binding and/or transcriptionally activating small molecules have produced limited Nurr1-specific compound scaffolds and have not yet provided potent, high affinity Nurr1-specific ligands. An alternative approach to regulate Nurr1 activity that has gained momentum is targeting Nurr1-RXR heterodimer complexes via small molecule ligands that bind to the RXR LBD. In this project, we will build on our strong preliminary data and develop biochemical and cellular assays that detect ligand-induced changes in Nurr1-RXR activity. The successful outcomes of our studies will provide a platform to screen, discover, and characterize Nurr1-RXR selective ligands that can be used as chemical tools to study Nurr1-RXR modulation in models of Alzheimer’s disease, Parkinson’s disease, and other aging-associated neurodegenerative and dementia disorders.