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Identification and characterization of small molecule modulators of the EBI2 receptor

Gessier, Francois and Preuss, Inga and Yin, Hong and Rosenkilde, Mette and Laurent, Stephane and Endres, Ralf and Chen, Yu and Marsilje, Thomas and Seuwen, Klaus and Nguyen, Deborah and Sailer, Andreas (2014) Identification and characterization of small molecule modulators of the EBI2 receptor. Journal of Medicinal Chemistry, 57. pp. 3358-3368.

Abstract

Oxysterols such as 7a, 25-dihydroxycholesterol (7a,25-OHC) have recently been identified as natural ligands for a G protein-coupled receptor called Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183) 1, 2. EBI2 is highly expressed in immune cells 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 3. In order to further delineate the physiological role of the oxysterol/EBI2 pathway in health and disease, here we describe the isolation and characterization of a potent small molecule antagonist for the EBI2 receptor. Prior to the isolation of the natural ligand, we first identified a surrogate small molecule agonist NIBR51 (NVP-AIU198) 1, which enabled identification of inhibitors of receptor activation. One antagonist called NIBR127 (NVP-AQV967) 2 was used as a starting point for a medicinal chemistry campaign which yielded NIBR189 (NVP-CHY976) 4m. This compound was extensively characterized in binding and various functional signaling assays to show that it is a potent and selective antagonist for the EBI2 receptor. Furthermore we have used NIBR189 (NVP-CHY976) 4m to block migration of a monocyte cell line called U937, suggesting a functional role of the oxysterol/EBI2 pathway in these immune cells.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/20482

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