Selective modulators for the nuclear receptor Nurr1

核受体 Nurr1 的选择性调节剂

基本信息

批准号：
9975246
负责人：
Pamela Michael England
金额：
$ 35.33万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975246
关键词：
Agonist Amodiaquine Antimalarials Aromatic Amino Acids Binding Binding Sites Biological Assay Biology Biophysics Brain-Derived Neurotrophic Factor Cells Cellular Assay Chemicals Complex Crystallization Cysteine DNA Binding Domain DNA Sequence Data Development Disease Disease Progression Disulfides Dopamine FDA approved Foundations Foxes GDNF receptors Gene Expression Genes Genetic Transcription Homeostasis Human Human Development In Vitro Individual Learning Legal patent Ligand Binding Ligand Binding Domain Ligands Literature Maintenance Midbrain structure Molecular Conformation Neurodegenerative Disorders Nuclear Receptors Nurr1 nuclear receptor Orphan Oxidative Stress Parkinson Disease Pharmaceutical Preparations Pharmacology Physiological Play Polymers Proteins Publishing RXR RXRA gene Reaction Regulation Reporting Research Roentgen Rays Role Side Signal Transduction Structure Symptoms Technology Therapeutic Work X-Ray Crystallography Zebrafish adduct analog dimer dopaminergic neuron drug development gene synthesis in vivo monomer motor deficit nervous system disorder programs receptor reuptake scaffold screening small molecule therapeutic target tool transcription factor

项目摘要

PROJECT SUMMARY Nuclear receptors are a superfamily of ligand-regulated transcription factors that play fundamental roles in human development, homeostasis, and disease. These receptors interact with small molecules, protein partners, and DNA sequences to regulate the transcription of specific target genes. Developing ligands that stabilize specific conformational states of the receptor, and thus drive the transcription of specific target genes, is a prerequisite for developing effective nuclear receptor therapeutics. The nuclear receptor Nurr1 (NR4A2) is widely recognized as a therapeutic target for Parkinson's disease, potentially modifying both the symptoms and progression of the disease. Current therapeutics for Parkinson's disease are symptom-modifying only and lose efficacy as the disease progresses. Although “Nurr1 agonists” have been reported in both the scientific and patent literature, there is little evidence these ligands directly activate the receptor. The only published crystal structure of Nurr1 reveals two distinctive features that have hindered progress developing small molecules targeting this receptor: Nurr1 lacks both the canonical nuclear receptor ligand binding pocket and the classical binding site for protein partners. Using an orthogonal drug development strategy called disulfide-trapping, we identified ~50 small molecules that bind directly to Nurr1 and form covalent adducts with a native cysteine residue in the ligand binding domain. We also identified an endogenous ligand that forms a reversible covalent adduct with the same cysteine residue. Co-crystal structures for three of these ligand-receptor complexes show Nurr1 in three distinctly different conformations. The proposed research will capitalize on these findings to develop chemical probes for Nurr1 that can be used to unravel the receptor's complex biology. Successful completion of these aims will define the relationships between individual ligand scaffolds, Nurr1 conformational states, and specific Nurr1 target genes, thereby providing the foundation for rationally developing new PD therapeutics. In Aim 1, we will generate covalent ligands for Nurr1, suitable for cellular assays, and use them to identify the target genes associated with different conformational states of the receptor. In Aim 2, we will identify functional analogs of the endogenous Nurr1 ligand that will enable cellular studies probing the receptor's regulation. In Aim 3, we will identify ligands that stabilize additional conformations of the receptor (e.g. heterodimer with RXR) and solve co-crystal structures of the resulting Nurr1 complexes.

项目概要核受体是配体调节转录因子的超家族，在这些受体与小分子、蛋白质相互作用。合作伙伴和 DNA 序列来调节特定靶基因的转录。稳定受体的特定构象状态，从而驱动特定靶基因的转录，是开发有效的核受体疗法的先决条件。核受体 Nurr1 (NR4A2) 被广泛认为是帕金森病的治疗靶点，可能改变帕金森病的症状和进展。尽管“Nurr1 激动剂”仅能缓解症状，但随着疾病的进展会失去疗效。科学和专利文献均已报道，但几乎没有证据表明这些配体直接唯一发表的 Nurr1 晶体结构揭示了两个独特的特征：阻碍针对该受体的小分子的发展进展：Nurr1 缺乏规范的核受体配体结合口袋和蛋白质伴侣的经典结合位点。使用称为二硫键捕获的正交药物开发策略，我们鉴定了约 50 个小分子直接与 Nurr1 结合并与配体结合中的天然半胱氨酸残基形成共价加合物我们还鉴定了与相同结构域形成可逆共价加合物的内源配体。这些配体-受体复合物中的三个的共晶结构显示了三个中的 Nurr1。拟议的研究将利用这些发现来开发化学物质。 Nurr1 探针可用于解开受体的复杂生物学过程成功完成这些任务。目标将定义各个配体支架、Nurr1构象状态和特定配体之间的关系 Nurr1靶基因，从而为合理开发PD新疗法提供基础。在目标 1 中，我们将为 Nurr1 生成适合细胞测定的共价配体，并用它们来识别与受体不同构象状态相关的靶基因。在目标 2 中，我们将鉴定内源性 Nurr1 配体的功能类似物，以实现细胞研究探索受体的调节。在目标 3 中，我们将鉴定能够稳定受体其他构象的配体（例如异二聚体） RXR) 并解析所得 Nurr1 复合物的共晶结构。