High throughput screening for compounds to the orphan nuclear receptor NR2F6.
High throughput screening for compounds to the orphan nuclear receptor NR2F6.
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DOI：
10.1016/j.slasd.2022.03.005
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发表时间：
2022-06
期刊：
影响因子：
3.1
通讯作者：
Solt, Laura A.
中科院分区：
文献类型：
--
作者：
Smith, Emery;Campbell, Sean;Wilson, Adrianna N.;Shumate, Justin;Baillargeon, Pierre;Scampavia, Louis;Kamenecka, Theodore M.;Spicer, Timothy P.;Solt, Laura A.
NR2F6被认为是孤儿核受体，因为其内源性配体尚未被鉴定。最近，NR2F6已成为一种新的癌症治疗靶点。NR2F6已被证明在几种癌症中上调或过表达。重要的是，Nr2f6 −/−小鼠自发地排斥肿瘤并产生宿主保护性免疫记忆，这是NR2F6在效应T细胞中充当免疫检查点的结果。总的来说，这些数据表明NR2F6活性的调节可能在对抗癌症中具有重要的临床应用。配体调节转录因子的核受体超家族已被证明是多种疾病治疗干预的绝佳靶点来源。大约15%的FDA批准的药物靶向NR，证明了它们的临床疗效。为了鉴定NR2F6活性的小分子调节剂，以免疫肿瘤学为总体目标，我们开发并启动了一种高通量的基于细胞的测定，该测定专门测量NR2F6的转录活性。我们完成了大约666，000种化合物的自动筛选，并确定了5，008个初始命中。进一步的筛选工作，包括反筛选试验，确认了其中128个命中，其中大多数的IC 50等于或小于5 μ M效价。在这里，我们报告，为第一次，几个小分子化合物的孤儿核受体，NR2F6的鉴定。
NR2F6 is considered an orphan nuclear receptor since its endogenous ligand has yet to be identified. Recently, NR2F6 has emerged as a novel cancer therapeutic target. NR2F6 has been demonstrated to be upregulated or overexpressed in several cancers. Importantly, Nr2f6−/− mice spontaneously reject tumors and develop host-protective immunological memory, a consequence of NR2F6 acting as an immune checkpoint in effector T cells. Collectively, these data suggest that modulation of NR2F6 activity may have important clinical applications in the fight against cancer. The nuclear receptor superfamily of ligand-regulated transcription factors has proven to be an excellent source of targets for therapeutic intervention of a broad range of diseases. Approximately 15% of FDA approved drugs target NRs, demonstrating their clinical efficacy. To identify small molecule regulators of NR2F6 activity, with the overall goal of immuno-oncology, we developed and initiated a high-throughput cell-based assay that specifically measures the transcriptional activity of NR2F6. We completed automated screening of approximately 666,000 compounds and identified 5,008 initial hits. Further screening efforts, including counterscreening assays, confirmed 128 of these hits, most of which had IC50s of equal to or less than 5μM potencies. Here, we report, for the first time, the identification of several small molecule compounds to the orphan nuclear receptor, NR2F6.
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