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Ligand biased and probe-dependent modulation of the chemokine receptor CXCR3 signaling by negative allosteric modulators

Bernat, Viachaslau and Brox, Regine and Heinrich, Markus and Auberson, Yves and Tschammer, Nuska (2014) Ligand biased and probe-dependent modulation of the chemokine receptor CXCR3 signaling by negative allosteric modulators. ChemMedChem, 10 (3). pp. 566-574. ISSN 18607179

Abstract

Over the last decade functional selectivity (or bias) has evolved from being a peculiar phenomenon to being recognized as an essential feature of synthetic ligands targeting G protein-coupled receptors (GPCRs). The chemokine receptor CXCR3 is an outstanding platform to study various aspects of biased signaling, because nature itself uses functional selectivity to manipulate the receptor signaling. At the same time CXCR3 is an attractive therapeutic target in autoimmune diseases and cancer. Here we report the discovery of a small molecule (1b) that can selectively inhibit CXCL11-dependent G protein activation over β-arrestin recruitment (with a 190-fold selectivity). The compound also demonstrates probe-dependent activity, i.e. it inhibits CXCL11- over CXCL10-mediated G protein activation with a 12-fold selectivity. Together with previously reported biased negative allosteric modulator from our group, the present study provides additional support to our hypothesis of multiple binding orientations for synthetic ligands of CXCR3.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/24369

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