Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
Department of Pharmacy, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377, Munich, Germany.
ChemMedChem. 2022 Aug 17;17(16):e202200259. doi: 10.1002/cmdc.202200259. Epub 2022 Jul 7.
The neuron derived orphan receptor (NOR-1, NR4A3) is among the least studied nuclear receptors. Its physiological role and therapeutic potential remain widely elusive which is in part due to the lack of chemical tools that can directly modulate NOR-1 activity. To probe the possibility of pharmacological NOR-1 modulation, we have tested a drug fragment library for NOR-1 activation and repression. Despite low hit-rate (<1 %), we have obtained three NOR-1 ligand chemotypes one of which could be rapidly expanded to an analogue comprising low micromolar inverse NOR-1 agonist potency and altering NOR-1 regulated gene expression in a cellular setting. It confirms druggability of the transcription factor and may serve as an early tool to assess the role and potential of NOR-1.
神经元衍生孤儿受体（NOR-1，NR4A3）是研究最少的核受体之一。其生理作用和治疗潜力仍然广泛难以捉摸，部分原因是缺乏可以直接调节 NOR-1 活性的化学工具。为了探究药理学 NOR-1 调节的可能性，我们测试了一个用于 NOR-1 激活和抑制的药物片段文库。尽管命中率较低（<1%），我们已经获得了三种 NOR-1 配体化学类型，其中一种可以快速扩展为包含低微摩尔反向 NOR-1 激动剂效力的类似物，并在细胞环境中改变 NOR-1 调节的基因表达。它证实了转录因子的可药性，并可能作为评估 NOR-1 的作用和潜力的早期工具。
