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：
10452585
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452585
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 NR4A2 gene Neurodegenerative Disorders Nuclear Receptors 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.

项目摘要核接收器是配体调节的转录因子的超家族，在人类发展，稳态和疾病。这些受体与小分子相互作用，蛋白质伴侣和DNA序列调节特定靶基因的转录。开发配体稳定接收器的特定会议状态，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。核接收器Nurr1（NR4A2）被广泛认为是帕金森氏病的治疗靶标，有可能改变疾病的症状和进展。当前对帕金森氏症的疗法疾病仅在症状调整，随着疾病进展而失去效率。虽然“ Nurr1激动剂” 在科学文献和专利文献中都有报道，这些配体直接几乎没有证据激活接收器。 Nurr1的唯一发表的晶体结构揭示了两个具有的不同特征阻碍了发展针对此接收器的小分子的进展：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。我们使用称为二硫键诱捕的正交药物开发策略，我们确定了〜50个小分子直接与Nurr1结合并形成共价加合物，并在配体结合中与天然半胱氨酸居住领域。我们还确定了一种内源性配体，形成可逆的共价加合物，半胱氨酸居住。这些配体 - 受体复合物中三个的共结晶结构显示了三个中的Nurr1 明显不同的考虑因素。拟议的研究将利用这些发现以开发化学 NURR1的问题可用于揭示接收者的复杂生物学。这些成功完成目标将定义单个配体支架，NurR1构象状态与特定的关系之间的关系 NURR1靶基因，从而为合理发展新的PD疗法提供了基础。在AIM 1中，我们将生成Nurr1的共价配体，适合细胞测定，并使用它们来识别与接收器的不同构象状态相关的靶基因。在AIM 2中，我们将确定内源性Nurr1配体的功能类似物，该配体将使细胞研究能够探测接收器的法规。在AIM 3中，我们将确定可以稳定接收器的其他构象的配体（例如 RXR）和求解所得Nurr1复合物的共结晶结构。