ACS Chem Biol. 2011 Feb 18;6(2):131-4. doi: 10.1021/cb1002575. Epub 2010 Nov 10.
REV-ERBα is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBα suppresses transcription of its target genes in a heme-dependent manner. Recently, the first nonporphyrin synthetic ligand for REV-ERBα, GSK4112, was designed, and it mimics the action of heme acting as agonist. Here, we report the identification of the first REV-ERB antagonist, SR8278. SR8278 is structurally similar to the agonist but blocks the ability of the GSK4112 to enhance REV-ERBα-dependent repression in a cotransfection assay. Additionally, whereas GSK4112 suppresses the expression of REV-ERBα target genes involved in gluconeogenesis, SR8278 stimulates the expression of these genes. Thus, SR8278 represents a unique chemical tool for probing REV-ERB function and may serve as a point for initiation of further optimization to develop REV-ERB antagonists with the ability to explore circadian and metabolic functions.
REV-ERBα 是核受体超家族的一员，作为卟啉血红素的受体发挥作用。REV-ERBα 以血红素依赖的方式抑制其靶基因的转录。最近，第一个非卟啉的 REV-ERBα 合成配体 GSK4112 被设计出来，它模拟血红素的作用作为激动剂。在这里，我们报告了第一个 REV-ERB 拮抗剂 SR8278 的鉴定。SR8278 的结构与激动剂相似，但在共转染测定中阻断了 GSK4112 增强 REV-ERBα 依赖性抑制的能力。此外，虽然 GSK4112 抑制参与糖异生的 REV-ERBα 靶基因的表达，但 SR8278 刺激这些基因的表达。因此，SR8278 代表了一种用于探测 REV-ERB 功能的独特化学工具，并且可能作为进一步优化以开发具有探索昼夜节律和代谢功能能力的 REV-ERB 拮抗剂的起点。
