Small-Molecule Fluorescent Ligands for the CXCR4 Chemokine Receptor

Dekkers, Sebastian; Caspar, Birgit; Goulding, Joëlle; Kindon, Nicholas D; Kilpatrick, Laura E.; Stoddart, Leigh A; Briddon, Stephen J.; Kellam, Barrie; Hill, Stephen J.; Stocks, Michael J.

Abstract

The C-X-C chemokine receptor type 4, or CXCR4, is a chemokine receptor found to promote cancer progression and metastasis of various cancer cell types. To investigate the pharmacology of this receptor, and to further elucidate its role in cancer, novel chemical tools are a necessity. In the present study, using classic medicinal chemistry approaches, small-molecule-based fluorescent probes were designed and synthesized based on previously reported small-molecule antagonists. Here, we report the development of three distinct chemical classes of fluorescent probes that show specific binding to the CXCR4 receptor in a novel fluorescence-based NanoBRET binding assay (pKD ranging 6.6-7.1). Due to their retained affinity at CXCR4, we furthermore report their use in competition binding experiments and confocal microscopy to investigate the pharmacology and cellular distribution of this receptor.

Citation

Dekkers, S., Caspar, B., Goulding, J., Kindon, N. D., Kilpatrick, L. E., Stoddart, L. A., …Stocks, M. J. (2023). Small-Molecule Fluorescent Ligands for the CXCR4 Chemokine Receptor. Journal of Medicinal Chemistry, 66(7), 5208-5222. https://doi.org/10.1021/acs.jmedchem.3c00151

• Journal Article Type: Article
• Acceptance Date: Mar 9, 2023
• Online Publication Date: Mar 21, 2023
• Publication Date: Apr 13, 2023
• Deposit Date: Mar 10, 2023
• Publicly Available Date: Mar 22, 2024
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Peer Reviewed: Peer Reviewed
• Volume: 66
• Issue: 7
• Pages: 5208-5222
• DOI: https://doi.org/10.1021/acs.jmedchem.3c00151
• Keywords: Antagonists, Fluorescence, Ligands, Mixtures, Receptors
• Public URL: https://nottingham-repository.worktribe.com/output/18236216
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00151
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Journal of Medicinal Chemistry after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00151