Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor
Research output: Contribution to journal › Journal article › peer-review
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.
|Journal||Journal of Medicinal Chemistry|
|Number of pages||11|
|Publication status||Published - 24 Apr 2014|
- Animals, CHO Cells, Calcium, Cricetulus, Herpesvirus 4, Human, Humans, Male, Mice, Mice, Inbred C57BL, Receptors, G-Protein-Coupled, U937 Cells