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Modulators of CXCR4 and CXCR7/ACKR3 Function

Adlere, Ilze; Caspar, Birgit; Arimont, Marta; Dekkers, Sebastian; Visser, Kirsten; Stuijt, Jeffrey; de Graaf, Chris; Stocks, Michael; Kellam, Barrie; Briddon, Stephen; Wijtmans, Maikel; de Esch, Iwan; Hill, Stephen; Leurs, Rob


Ilze Adlere

Birgit Caspar

Marta Arimont

Sebastian Dekkers

Kirsten Visser

Jeffrey Stuijt

Chris de Graaf

Professor of Medicinal Chemistry and Drug Discovery

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Professor of Medicinal Chemistry

Maikel Wijtmans

Iwan de Esch

Professor of Molecular Pharmacology

Rob Leurs


Copyright © 2019 by The Author(s). The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the small-molecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio- and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENT: To investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.


Adlere, I., Caspar, B., Arimont, M., Dekkers, S., Visser, K., Stuijt, J., …Leurs, R. (2019). Modulators of CXCR4 and CXCR7/ACKR3 Function. Molecular Pharmacology, 96(6), 737-752.

Journal Article Type Article
Acceptance Date Sep 14, 2019
Online Publication Date Sep 23, 2019
Publication Date Dec 1, 2019
Deposit Date Jan 13, 2020
Publicly Available Date Jan 14, 2020
Journal Molecular Pharmacology
Print ISSN 0026-895X
Electronic ISSN 1521-0111
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 96
Issue 6
Pages 737-752
Keywords Molecular Medicine; Pharmacology
Public URL


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