Discovery Technology and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D Center, Shanghai, China.
Mol Pharmacol. 2012 Oct;82(4):583-90. doi: 10.1124/mol.112.078667. Epub 2012 Jun 14.
In a screen for small-molecule inhibitors of retinoid acid-related orphan receptor γ (RORγ), we fortuitously discovered that a class of aryl amide compounds behaved as functional activators of the interleukin 17 (IL-17) reporter in Jurkat cells. Three of these compounds were selected for further analysis and found to activate the IL-17 reporter with potencies of ∼0.1 μM measured by EC₅₀. These compounds were shown to directly bind to RORγ by circular dichroism-based thermal stability experiments. Furthermore, they can enhance an in vitro Th17 differentiation process in human primary T cells. As RORγ remains an orphan nuclear receptor, discovery of these aryl amide compounds as functional agonists will now provide pharmacological tools for us to dissect functions of RORγ and facilitate drug discovery efforts for immune-modulating therapies.
在筛选视黄酸相关孤儿受体 γ（RORγ）小分子抑制剂的过程中，我们偶然发现了一类芳酰胺类化合物可以作为 Jurkat 细胞中白细胞介素 17（IL-17）报告基因的功能性激活剂。选择了其中的三种化合物进行进一步分析，发现它们可以通过 EC₅₀ 测量以约 0.1μM 的效力激活 IL-17 报告基因。圆二色性基于热稳定性实验表明，这些化合物可以直接与 RORγ 结合。此外，它们可以增强人原代 T 细胞中的体外 Th17 分化过程。由于 RORγ 仍然是一种孤儿核受体，这些芳酰胺化合物作为功能性激动剂的发现将为我们提供研究 RORγ 功能的药理学工具，并促进免疫调节治疗的药物发现工作。
