The ligand-activated transcription factor nuclear receptor related-1 (Nurr1) exhibits great potential for neurodegenerative disease treatment, but potent Nurr1 modulators to further probe and validate the nuclear receptor as a therapeutic target are lacking. We have systematically studied the structure–activity relationship of the 4-amino-7-chloroquinoline scaffold contained in Nurr1 activators amodiaquine and chloroquine and discovered fragment-like analogues that activated Nurr1 in several cellular settings. The most active descendants promoted the transcriptional activity of Nurr1 on human response elements as monomer, homodimer, and heterodimer and markedly enhanced Nurr1-dependent gene expression in human astrocytes. As a tool to elucidate mechanisms involving in Nurr1 activation, these Nurr1 agonists induced robust recruitment of NCoR1 and NCoR2 co-regulators to the Nurr1 ligand binding domain and promoted Nurr1 dimerization. These findings provide important insights in Nurr1 regulation. The fragment-sized Nurr1 agonists are appealing starting points for medicinal chemistry and valuable early Nurr1 agonist tools for pharmacology and chemical biology.

中文翻译：

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片段样氯喹啉胺激活孤儿核受体Nurr1和阐明激活机制。

配体激活的转录因子核受体相关-1（Nurr1）在神经退行性疾病的治疗中显示出巨大的潜力，但是还缺乏有效的Nurr1调节剂来进一步探测和验证核受体作为治疗靶标。我们已经系统地研究了Nurr1激活剂氨二喹和氯喹中所含的4-氨基-7-氯喹支架的结构-活性关系，并发现了在多个细胞环境中激活Nurr1的类似片段的类似物。最活跃的后代在人类星形胶质细胞中促进了Nurr1在人类反应元件上的转录活性，如单体，同二聚体和异二聚体，并显着增强了Nurr1依赖性基因的表达。作为阐明涉及Nurr1激活的机制的工具，这些Nurr1激动剂可诱导NCoR1和NCoR2协同调节剂稳固募集至Nurr1配体结合域，并促进Nurr1二聚化。这些发现为Nurr1调控提供了重要的见识。片段大小的Nurr1激动剂是药物化学的诱人起点，也是药理学和化学生物学领域有价值的早期Nurr1激动剂工具。