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

TY - JOUR

T1 - Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor

AU - Gessier, Francois

AU - Preuss, Inga

AU - Yin, Hong

AU - Rosenkilde, Mette Marie

AU - Laurent, Stephane

AU - Endres, Ralf

AU - Chen, Yu A

AU - Marsilje, Thomas H

AU - Seuwen, Klaus

AU - Nguyen, Deborah G

AU - Sailer, Andreas W

PY - 2014/4/24

Y1 - 2014/4/24

N2 - 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.

AB - 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.

KW - Animals

KW - CHO Cells

KW - Calcium

KW - Cricetulus

KW - Herpesvirus 4, Human

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Receptors, G-Protein-Coupled

KW - U937 Cells

U2 - 10.1021/jm4019355

DO - 10.1021/jm4019355

M3 - Journal article

C2 - 24678947

SN - 0022-2623

VL - 57

SP - 3358

EP - 3368

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -