Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1,Journal of Medicinal Chemistry

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Development and Profiling of Inverse Agonist Tools for the Neuroprotective Transcription Factor Nurr1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-11 , DOI: 10.1021/acs.jmedchem.1c01077
Daniel Zaienne ₁ , Sabine Willems ₁ , Simone Schierle ₁ , Jan Heering ₂ , Daniel Merk _{1,

3}

Affiliation

The ligand-sensing transcription factor nuclear receptor related 1 (Nurr1) evolves as an appealing target to treat neurodegenerative diseases. Despite its therapeutic potential observed in various rodent models, potent modulators for Nurr1 are lacking as pharmacological tools. Here, we report the structure–activity relationship and systematic optimization of indole-based inverse Nurr1 agonists. Optimized analogues decreased the receptor’s intrinsic transcriptional activity by up to more than 90% and revealed preference for inhibiting Nurr1 monomer activity. In orthogonal cell-free settings, we detected displacement of NCoRs and disruption of the Nurr1 homodimer as molecular modes of action. The inverse Nurr1 agonists reduced the expression of Nurr1-regulated genes in T98G cells, and treatment with an inverse Nurr1 agonist mimicked the effect of Nurr1 silencing on interleukin-6 release from LPS-stimulated human astrocytes. The indole-based inverse Nurr1 agonists valuably extend the toolbox of Nurr1 modulators to further probe the role of Nurr1 in neuroinflammation, cancer, and beyond.

中文翻译：

神经保护转录因子 Nurr1 反向激动剂工具的开发和分析

配体感应转录因子核受体相关 1 (Nurr1) 进化为治疗神经退行性疾病的有吸引力的靶点。尽管在各种啮齿动物模型中观察到其治疗潜力，但缺乏有效的 Nurr1 调节剂作为药理学工具。在这里，我们报告了基于吲哚的反向 Nurr1 激动剂的构效关系和系统优化。优化的类似物将受体的内在转录活性降低了 90% 以上，并显示出对抑制 Nurr1 单体活性的偏好。在正交无细胞环境中，我们检测到 NCoR 的置换和 Nurr1 同源二聚体的破坏作为分子作用模式。反向 Nurr1 激动剂降低了 T98G 细胞中 Nurr1 调节基因的表达，用反向 Nurr1 激动剂处理模拟了 Nurr1 沉默对 LPS 刺激的人星形胶质细胞释放白细胞介素 6 的影响。基于吲哚的反向 Nurr1 激动剂极大地扩展了 Nurr1 调节剂的工具箱，以进一步探索 Nurr1 在神经炎症、癌症等方面的作用。

更新日期：2021-10-28

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