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

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

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

J Med Chem. 2014 Apr 24;57(8):3358-68.

PMID: 24678947

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1599432082	NIBR189		1599432-08-2	Price

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