Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors

• DOI: 10.1002/cmdc.201200582
• Publication Date: 2013-03-06T17:57:52Z
• Authors: Suazette Reid Moo...; Jin Liu; Zhongxing Liang; Jeffrey Ahn; Samuel Hong; Younghyoun Yoon; James P. Snyder; Hyunsuk Shim
• Keywords: 0301 basic medicine; Receptors, CXCR4; Sulfonamides; Binding Sites; Pyridines; Chemokine CXCL12; Protein Structure, Tertiary; 3. Good health; Molecular Docking Simulation; Benzenesulfonamides; 03 medical and health sciences; Cell Line, Tumor; Drug Design; Humans; Protein Interaction Maps; Protein Binding

AbstractThe 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 in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC50=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency.