Selective modulators for the nuclear receptor Nurr1

核受体 Nurr1 的选择性调节剂

• 批准号: 10207800
• 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/10207800
• 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

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.

项目总结 核受体是配体调节的转录因子的超家族，在 人类发展、动态平衡和疾病。这些受体与小分子、蛋白质相互作用 伙伴，和DNA序列，以调节特定的靶基因的转录。发展中的配体 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Nurr1(NR4A2)被广泛认为是帕金森病的治疗靶点， 潜在地改变了疾病的症状和进展。帕金森氏症的现代治疗方法 疾病只是改变症状，随着疾病的发展而失效。虽然“Nurr1激动剂” 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 激活感受器。唯一发表的Nurr1的晶体结构揭示了两个不同的特征， 阻碍了针对该受体的小分子的开发：Nurr1既缺乏规范的核 受体配基结合口袋和蛋白质伙伴的经典结合部位。 使用一种名为二硫化物捕获的正交药物开发策略，我们鉴定了大约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 域。我们还鉴定了一种内源性配体，它与其形成可逆的共价加合物 半胱氨酸残留物。其中三个配体-受体络合物的共晶体结构显示三个 截然不同的构象。拟议中的研究将利用这些发现来开发化学物质。 探测Nurr1，可以用来解开受体的复杂生物学。成功完成这些任务 AIMS将定义单个配体支架、Nurr1构象状态和特定的 Nurr1靶基因，从而为合理开发新的PD治疗药物提供了基础。 在目标1中，我们将为Nurr1生成适合于细胞分析的共价配体，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，我们将确定内源性Nurr1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，我们将确定稳定受体额外构象的配体(例如，具有 RXR)，并解算得到的Nurr1配合物的共晶结构。