Modulators of CXCR4 and CXCR7/AckR3 function

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

*Corresponding author for this work

Research output: Contribution to JournalShort surveyAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)737-752
Number of pages16
JournalMolecular pharmacology
Issue number6
Publication statusPublished - 1 Dec 2019


This work was supported by European Union’s Horizon2020 MSCA Program under grant agreement 641833 [ONCORNET]. This minireview is part of the series “From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function.” 1I.A., B.C., and M.A. contributed equally to this work. s This article has supplemental material available at molpharm.aspetjournals. org.

FundersFunder number
European Union’s Horizon2020 MSCA641833


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