Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor

Research output: Contribution to journalJournal articlepeer-review

  • Francois Gessier
  • Inga Preuss
  • Hong Yin
  • Rosenkilde, Mette
  • Stephane Laurent
  • Ralf Endres
  • Yu A Chen
  • Thomas H Marsilje
  • Klaus Seuwen
  • Deborah G Nguyen
  • Andreas W Sailer

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.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number8
Pages (from-to)3358-68
Number of pages11
Publication statusPublished - 24 Apr 2014

    Research areas

  • Animals, CHO Cells, Calcium, Cricetulus, Herpesvirus 4, Human, Humans, Male, Mice, Mice, Inbred C57BL, Receptors, G-Protein-Coupled, U937 Cells

ID: 137818108