Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.

核受体相关 1 (Nurr1) 是一种孤儿配体激活转录因子，被认为是神经保护性转录调节因子，具有作为神经退行性疾病治疗靶点的巨大潜力。然而，可用的 Nurr1 调制器的收集和对 Nurr1 的机械理解是有限的。在这里，我们报告了几种结构不同的非甾体类抗炎药作为 Nurr1 反向激动剂的发现，证明 Nurr1 活性可以双向调节。作为化学工具，这些配体能够揭示 Nurr1 的共同调节网络以及区分激动剂和反向激动剂的作用模式。除了其二聚化能力外，我们还观察到 Nurr1 能够以配体依赖性方式募集多个典型核受体共调节因子。不同的二聚化状态和共调节相互作用模式作为 Nurr1 激动剂和反向激动剂的区分因素出现。我们的结果为未来的 Nurr1 目标验证和药物发现提供了有价值的 Nurr1 调制器集合和相关的机制见解。