The development of potent, competitive CXCR4 antagonists for the prevention of cancer metastasis

Hamshaw, Isabel ORCID:, Cominetti, Marco M. D., Lai, Wing-Yee, Searcey, Mark ORCID: and Mueller, Anja ORCID: (2023) The development of potent, competitive CXCR4 antagonists for the prevention of cancer metastasis. Biochemical Pharmacology, 218. ISSN 0006-2952

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Cancer metastasis is the cause of up to 90 % of cancer related mortality. The CXCR4 receptor and its cognate ligand, CXCL12, have major roles in enabling cancer metastasis and consequently, the CXCR4 receptor has become an attractive therapeutic target for the prevention of metastasis. Despite this, CXCR4 antagonists have had limited success in clinical trials due to cellular toxicity and poor stability and efficacy. In this study, we developed a novel, competitive CXCR4 antagonist (IS4) that through copper-catalysed-azide-alkyne-cycloaddition can be clicked to other chemical moieties such as fluorescent dyes (IS4-FAM) for CXCR4-based imaging. We determined that these CXCR4 antagonists were non-toxic and could be used to specifically label the CXCR4 receptor. Furthermore, IS4 and IS4-FAM inhibited both CXCL12-stimulated cancer cell migration and Ca2+ release in both adherent and suspension cell lines with similar or improved potency as compared to two literature CXCR4 antagonists. Our results highlight the potential of IS4 and IS4-FAM as research tools and as potent CXCR4 antagonists for the prevention of metastasis.

Item Type: Article
Uncontrolled Keywords: chemokine receptor,cxcl12,cxcr4,cxcr4 antagonist,maleimide,migration,biochemistry,pharmacology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1303
Faculty \ School: Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
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Depositing User: LivePure Connector
Date Deposited: 13 Nov 2023 18:01
Last Modified: 11 Apr 2024 23:55
DOI: 10.1016/j.bcp.2023.115921


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