Selective modulators for the nuclear receptor Nurr1

核受体 Nurr1 的选择性调节剂

• 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
• 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

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 核受体是配体调节的转录因子的超家族，其在以下方面发挥基本作用： 人类发展、体内平衡和疾病。这些受体与小分子、蛋白质 配偶体和DNA序列来调节特定靶基因的转录。开发配体， 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Nurr 1（NR 4A 2）被广泛认为是帕金森病的治疗靶点， 潜在地改变疾病的症状和进展。帕金森病的治疗现状 这些疾病仅是修饰性的，并且随着疾病的进展而失去功效。虽然“Nurr 1激动剂” 虽然在科学和专利文献中都有报道，但很少有证据表明这些配体直接 激活受体。唯一发表的Nurr 1晶体结构揭示了两个独特的特征， 阻碍了开发针对该受体的小分子的进展：Nurr 1缺乏典型的核 受体配体结合口袋和蛋白质伴侣的经典结合位点。 使用称为二硫化物捕获的正交药物开发策略，我们鉴定了约50种小分子 直接与Nurr 1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 域我们还鉴定了一种内源性配体，其与相同的配体形成可逆的共价加合物。 半胱氨酸残基。这些配体-受体复合物中的三种的共晶体结构显示Nurr 1在三种配体-受体复合物中的共晶体结构。 明显不同的构象。拟议中的研究将利用这些发现来开发化学品。 Nurr 1的探针，可用于解开受体的复杂生物学。成功完成这些 目标将定义单个配体支架、Nurr 1构象状态和特定配体之间的关系 Nurr 1靶向基因，从而为合理开发新的PD疗法提供基础。 在目标1中，我们将产生Nurr 1的共价配体，适用于细胞测定，并使用它们来鉴定 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Nurr 1配体的功能类似物，这将使细胞研究成为可能 探测受体的调节。 在目标3中，我们将鉴定稳定受体的另外构象的配体（例如，异二聚体， RXR）并解析所得Nurr 1复合物的共晶结构。