Chemokine receptor CXCR4 is a G protein-coupled receptor that, upon activation, induces a migratory movement of cells towards sites with a high concentration of CXCL12 (SDF-1α). Mostly these cells are of hematopoietic origin, migrating towards sites of inflammation. However it has been discovered that over 23 different types of cancer cells express this receptor, which use the CXCR4-CXCL12 signalling axis to migrate towards secondary tumour sites. The current toolkit available to study CXCR4 pharmacology comprises of (radiolabelled) small molecules, unlabelled and/or fluorescently labelled antibodies, and some peptides. With the aim to study the pharmacology of this receptor, as well as aid the development of novel therapeutics, we set out to expand the CXCR4 toolkit by developing small molecule-based fluorescent probes. Standard medicinal chemistry approaches were utilized to develop these fluorescent probes. A thorough evaluation of the described SAR, in combination with in silico design, informed our synthetic strategy to attach fluorescent dyes to previously reported CXCR4R antagonists. We successfully developed three distinct chemical classes of CXCR4 fluorescent antagonists, that show to be highly potent in a new fluorescence-based nanoBRET binding assay (pKD &gt; 6.8). We also demonstrate their utility in competition binding assays. With their high affinity for the receptor, as well as their good fluorescent properties, these compounds make excellent tools to study this receptor in vitro, and facilitate imaging techniques such as confocal microscopy and flow cytometry.

Expanding the pharmacological toolkit to study the CXCR4 receptor by developing fluorescent probes

255th National Meeting (2018)

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