Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor
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Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor. / Gessier, Francois; Preuss, Inga; Yin, Hong; Rosenkilde, Mette Marie; Laurent, Stephane; Endres, Ralf; Chen, Yu A; Marsilje, Thomas H; Seuwen, Klaus; Nguyen, Deborah G; Sailer, Andreas W.
I: Journal of Medicinal Chemistry, Bind 57, Nr. 8, 24.04.2014, s. 3358-68.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 57
SP - 3358
EP - 3368
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 8
ER -
ID: 137818108