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

• Published in: Journal of medicinal chemistry 2014-04, Vol.57 (8), p.3358-3368
• Main Authors: Gessier, Francois, Preuss, Inga, Yin, Hong, Rosenkilde, Mette M, Laurent, Stephane, Endres, Ralf, Chen, Yu A, Marsilje, Thomas H, Seuwen, Klaus, Nguyen, Deborah G, Sailer, Andreas W
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; CHO Cells; Cricetulus; Herpesvirus 4, Human; Humans; Male; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled - antagonists & inhibitors; U937 Cells
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm4019355

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.