Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2

Huber M, Wurnig S, Toy L, Weiler C, Merten N, Kostenis E, Hansen FK, Schiedel M (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Journal of Medicinal Chemistry American Chemical Society

DOI: 10.1021/acs.jmedchem.3c00769

Abstract

Herein, we report the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site (IABS) of CXC chemokine receptor 2 (CXCR2), a G protein-coupled receptor (GPCR) that has been pursued as a drug target in oncology and inflammation. Starting from the cocrystallized intracellular CXCR2 antagonist 00767013 (1), tetramethylrhodamine (TAMRA)-labeled CXCR2 ligands were designed, synthesized, and tested for their suitability as fluorescent reporters to probe binding to the IABS of CXCR2. By means of these studies, we developed Mz438 (9a) as a high-affinity and selective fluorescent CXCR2 ligand, enabling cell-free as well as cellular NanoBRET-based binding studies in a nonisotopic and high-throughput manner. Further, we show that 9a can be used as a tool to visualize intracellular target engagement for CXCR2 via fluorescence microscopy. Thus, our small-molecule-based fluorescent CXCR2 ligand 9a represents a promising tool for future studies of CXCR2 pharmacology.

Authors with CRIS profile

Max Huber Lehrstuhl für Pharmazeutische Chemie Lara Toy Lehrstuhl für Pharmazeutische Chemie Matthias Schiedel Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE)

How to cite

APA:

Huber, M., Wurnig, S., Toy, L., Weiler, C., Merten, N., Kostenis, E.,... Schiedel, M. (2023). Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2. Journal of Medicinal Chemistry. https://dx.doi.org/10.1021/acs.jmedchem.3c00769

MLA:

Huber, Max, et al. "Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2." Journal of Medicinal Chemistry (2023).

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