Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1,Journal of Medicinal Chemistry

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Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-08 , DOI: 10.1021/acs.jmedchem.0c00894
Paola Munoz-Tello ₁ , Hua Lin ₂ , Pasha Khan ₂ , Ian Mitchelle S de Vera ₁ , Theodore M Kamenecka ₂ , Douglas J Kojetin _{1,

2}

Affiliation

Nurr1/NR4A2 is an orphan nuclear receptor transcription factor implicated as a drug target for neurological disorders including Alzheimer’s and Parkinson’s diseases. Previous studies identified small-molecule NR4A nuclear receptor modulators, but it remains unclear if these ligands affect transcription via direct binding to Nurr1. We assessed 12 ligands reported to affect NR4A activity for Nurr1-dependent and Nurr1-independent transcriptional effects and the ability to bind the Nurr1 ligand-binding domain (LBD). Protein NMR structural footprinting data show that amodiaquine, chloroquine, and cytosporone B bind the Nurr1 LBD; ligands that do not bind include C-DIM12, celastrol, camptothecin, IP7e, isoalantolactone, ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), and three high-throughput screening hit derivatives. Importantly, ligands that modulate Nurr1 transcription also show Nurr1-independent effects on transcription in a cell type-specific manner, indicating that care should be taken when interpreting the functional response of these ligands in transcriptional assays. These findings should help focus medicinal chemistry efforts that desire to optimize Nurr1-binding ligands.

中文翻译：

直接结合和调节孤儿核受体 Nurr1 的 NR4A 配体的评估

Nurr1/NR4A2 是一种孤儿核受体转录因子，可作为阿尔茨海默病和帕金森病等神经系统疾病的药物靶点。先前的研究鉴定了小分子 NR4A 核受体调节剂，但尚不清楚这些配体是否通过直接结合 Nurr1 来影响转录。我们评估了 12 个据报告影响 NR4A 活性的配体，以实现 Nurr1 依赖性和 Nurr1 独立转录效应以及结合 Nurr1 配体结合域 (LBD) 的能力。蛋白质 NMR 结构足迹数据显示阿莫地喹、氯喹和细胞孢菌素 B 结合 Nurr1 LBD；不结合的配体包括C-DIM12、雷公藤红素、喜树碱、IP7e、异木香内酯、2-[2,3,4-三甲氧基-6-(1-辛酰基)苯基]乙酸乙酯(TMPA)，以及三个高通量筛选命中衍生品。重要的是，调节 Nurr1 转录的配体还以细胞类型特异性的方式显示出 Nurr1 独立的转录效应，这表明在转录测定中解释这些配体的功能反应时应小心。这些发现应该有助于集中精力优化 Nurr1 结合配体的药物化学工作。

更新日期：2020-12-24

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