神经保护性转录因子核受体相关 1 (Nurr1) 作为帕金森病、阿尔茨海默病以及多发性硬化症的治疗靶点显示出巨大的前景，但用于 Nurr1 药理学靶点验证的高质量化学工具却很少。我们采用弱 Nurr1 调节剂阿莫地喹 (AQ) 和 AQ 衍生片段作为模板，通过支架跳跃和片段生长策略设计新的 Nurr1 激动剂化学型。该支架的系统结构优化产生了具有纳摩尔效力和结合亲和力的 Nurr1 激动剂。全面的体外分析揭示了有效的细胞靶点参与并符合最高的探针标准。在携带帕金森驱动 LRRK2 突变的人类中脑类器官中，一种新型 Nurr1 激动剂挽救了酪氨酸羟化酶的表达，突显了新的 Nurr1 调节剂化学型作为先导和生物学研究化学工具的潜力。© 2024。作者。

The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.© 2024. The Author(s).