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

Authors

Sebastian Dekkers

Birgit Caspar

JOELLE GOULDING JOELLE.GOULDING@NOTTINGHAM.AC.UK
Research Fellow

NICHOLAS KINDON Nicholas.Kindon@nottingham.ac.uk
Research Fellow

Doctor LAURA KILPATRICK Laura.Kilpatrick@nottingham.ac.uk
Anne Mclaren Research Fellow

Leigh A Stoddart

STEPHEN BRIDDON stephen.briddon@nottingham.ac.uk
Principal Research Fellow

BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry

STEPHEN HILL steve.hill@nottingham.ac.uk
Professor of Molecular Pharmacology

MICHAEL STOCKS MICHAEL.STOCKS@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry and Drug Discovery

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. (in press). Small molecule fluorescent ligands for the CXCR4 chemokine receptor. Journal of Medicinal Chemistry,

Journal Article Type	Article
Acceptance Date	Mar 9, 2023
Deposit Date	Mar 10, 2023
Journal	Journal of Medicinal Chemistry
Print ISSN	0022-2623
Electronic ISSN	1520-4804
Publisher	American Chemical Society
Peer Reviewed	Peer Reviewed
Keywords	Chemokine receptor; CXCR4; fluorescent probes; BODIPY; NanoBRET
Public URL	https://nottingham-repository.worktribe.com/output/18236216
Publisher URL	https://pubs.acs.org/journal/jmcmar
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 DOI URL.