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 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.

癌症转移是高达 90% 的癌症相关死亡的原因。 CXCR4受体及其同源配体CXCL12在促进癌症转移方面发挥着重要作用，因此，CXCR4受体已成为预防转移的有吸引力的治疗靶点。尽管如此，CXCR4拮抗剂由于细胞毒性以及稳定性和疗效较差，在临床试验中取得的成功有限。在这项研究中，我们开发了一种新型的竞争性 CXCR4 拮抗剂 (IS4)，通过铜催化的叠氮化物-炔环加成反应，可以将其点击到其他化学部分，例如荧光染料 (IS4-FAM)，用于基于 CXCR4 的成像。我们确定这些CXCR4拮抗剂是无毒的，可用于特异性标记CXCR4受体。此外，与两种文献CXCR4拮抗剂相比，IS4和IS4-FAM抑制贴壁细胞系和悬浮细胞系中CXCL12刺激的癌细胞迁移和Ca ²⁺释放，具有相似或改进的效力。我们的结果强调了 IS4 和 IS4-FAM 作为研究工具和作为有效的 CXCR4 拮抗剂预防转移的潜力。