Probing the CXCR6/CXCL16 Axis: Targeting Prevention of Prostate Cancer Metastasis

Excerpt

Prostate cancer (PCa) has been cited as the second leading cause of cancer-related death in American men and its morbidity/mortality has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues especially to bone. Nearly 10% of patients whose conditions are diagnosed as PCa clinically present with bone metastasis and almost all patients who die of prostate cancer have skeletal involvement. Identifying new mechanisms that control bone metastasis is of great consequence to facilitate the design of therapeutics aimed at decreasing metastatic risk and/or resulting secondary complications. We completed an interrogation of the Molecular Libraries Small Molecule Repository (MLSMR) for antagonists of the CXCR6 receptor in cell-based functional assay. Here, we report for the first time a novel potent (140 nM IC₅₀) small molecule CXCR6 antagonist that is selective (>79 μM IC₅₀) against CXCR5, CXCR4, CCR6 and APJ receptors. It is non-promiscuous against 23 other G protein-coupled receptors (GPCRs), showing only moderate activity against 5-HT2B and DAT at 10 μM in competitive binding assays. This probe will assist in addressing a key hypothesis that the CXCR6/CXCL16 axis significantly contributes to PCa cell metastasis, proliferation and subsequent bone invasion. A small molecule antagonist would block cancer cell trafficking; hence mediate a metastatic event and disease progression. Access to pharmacologically available small molecule antagonists will ultimately enable our targeted studies in disease relevant models and allow for a more seamless translational advancement toward clinical applications.