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

Francois Gessier; Inga Preuss; Hong Yin; Mette Marie Rosenkilde; Stephane Laurent; Ralf Endres; Yu A Chen; Thomas H Marsilje; Klaus Seuwen; Deborah G Nguyen; Andreas W Sailer

doi:10.1021/jm4019355

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

Francois Gessier, Inga Preuss, Hong Yin, Mette Marie Rosenkilde, Stephane Laurent, Ralf Endres, Yu A Chen, Thomas H Marsilje, Klaus Seuwen, Deborah G Nguyen, Andreas W Sailer

27 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	8
Pages (from-to)	3358-68
Number of pages	11
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm4019355
Publication status	Published - 24 Apr 2014

Keywords

Animals
CHO Cells
Calcium
Cricetulus
Herpesvirus 4, Human
Humans
Male
Mice
Mice, Inbred C57BL
Receptors, G-Protein-Coupled
U937 Cells

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm4019355

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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.",

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author = "Francois Gessier and Inga Preuss and Hong Yin and Rosenkilde, {Mette Marie} and Stephane Laurent and Ralf Endres and Chen, {Yu A} and Marsilje, {Thomas H} and Klaus Seuwen and Nguyen, {Deborah G} and Sailer, {Andreas W}",

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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

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DO - 10.1021/jm4019355

M3 - Journal article

C2 - 24678947

SN - 0022-2623

VL - 57

SP - 3358

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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