GSK4112, a Small Molecule Chemical Probe for the Cell Biology of the Nuclear Heme Receptor Rev-erbα
GSK4112, a Small Molecule Chemical Probe for the Cell Biology of the Nuclear Heme Receptor Rev-erbα
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DOI：
10.1021/cb100141y
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发表时间：
2010-10-01
影响因子：
4
通讯作者：
Zuercher, William J.
中科院分区：
文献类型：
--
作者：
Grant, Daniel;Yin, Lei;Zuercher, William J.
孤儿核受体rev - erbb α的非卟啉配体的鉴定将使其作为血红素传感器和代谢和昼夜节律信号调节器的作用的研究成为可能。我们描述了一种生化试验的发展，测量Rev-erba和核受体共抑制因子-1 （NCoR）的肽之间的相互作用。利用该方法鉴定Rev-erba的小分子配体GSK4112(1)，该配体与血红素具有竞争性。在细胞中，1作为Rev-erb - α激动剂在细胞中抑制昼夜节律靶基因bmal1的表达。此外，1抑制肝细胞中糖异生基因的表达，降低原代肝细胞的葡萄糖输出。因此，1是一种有用的化学工具，可以探索rev - erbb α在转录抑制、昼夜节律生物学调节和代谢途径中的功能。此外，1可以作为设计具有体内药理活性的Rev-erba化学探针的起点。
The identification of nonporphyrin ligands for the orphan nuclear receptor Rev-erb alpha will enable studies of its role as a heme sensor and regulator of metabolic and circadian signaling. We describe the development of a biochemical assay measuring the interaction between Rev-erba and a peptide from the nuclear receptor corepressor-1 (NCoR). The assay was utilized to identify a small molecule ligand for Rev-erba, GSK4112 (1), that was competitive with heme. In cells, 1 profiled as a Rev-erb alpha agonist in cells to inhibit expression of the circadian tar, get gene bmal1. In addition, 1 repressed the expression of gluconeogenic genes in liver cells and reduced glucose output in primary hepatocytes. Therefore, 1 is useful as a chemical tool to probe the function of Rev-erb alpha in transcriptional repression, regulation of circadian biology, and metabolic pathways. Additionally, 1 may serve as a starting point for design of Rev-erba chemical probes with In vivo pharmacological activity.