title: Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor.
abstract: 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.
authors.affiliation: Global Discovery Chemistry; ‡Developmental & Molecular Pathways, §Analytical Sciences, Novartis Institutes for BioMedical Research , Basel 4002, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Gessier
authors.forename: Inga
authors.initials: I
authors.lastname: Preuss
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.forename: Stephane
authors.initials: S
authors.lastname: Laurent
authors.forename: Ralf
authors.initials: R
authors.lastname: Endres
authors.forename: Yu A
authors.initials: YA
authors.lastname: Chen
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Marsilje
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Nguyen
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D004854:Herpesvirus 4, Human; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D020298:U937 Cells
chemical_list: C080105:GPR183 protein, human; D043562:Receptors, G-Protein-Coupled; D002118:Calcium