Benzenesulfonamides: A Unique Class of Chemokine Receptor Type4 Inhibitors

The interaction of CXCR4 with CXCL12 (SDF-1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X-ray structure and to rationalize discrepancies between the affinity and Matrigel invitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0nM) and the Matrigel invasion assay (100% blockade of invasion at 10nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency. [PUBLICATION ABSTRACT]