Identification and Characterization of Small Molecule Modulators of the Epstein鈥揃arr Virus-Induced Gene 2 (EBI2) Receptor

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• 作者：Francois Gessier ; Inga Preuss ; Hong Yin ; Mette M. Rosenkilde ; Stephane Laurent ; Ralf Endres ; Yu A. Chen ; Thomas H. Marsilje ; Klaus Seuwen ; Deborah G. Nguyen ; Andreas W. Sailer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3358-3368
• 全文大小：403K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

Oxysterols have recently been identified as natural ligands for a G protein-coupled receptor called EBI2 (aka GPR183) ( Nature 2011, 475, 524; 519). EBI2 is highly expressed in immune cells ( J. Biol. Chem. 2006, 281, 13199), and its activation has been shown to be critical for the adaptive immune response and has been genetically linked to autoimmune diseases such as type I diabetes ( Nature 2010, 467, 460). Here we describe the isolation of a potent small molecule antagonist for the EBI2 receptor. First, we identified a small molecule agonist NIBR51 (1), which enabled identification of inhibitors of receptor activation. One antagonist called NIBR127 (2) was used as a starting point for a medicinal chemistry campaign, which yielded NIBR189 (4m). This compound was extensively characterized in binding and various functional signaling assays. Furthermore, we have used 4m to block migration of a monocyte cell line called U937, suggesting a functional role of the oxysterol/EBI2 pathway in these immune cells.