title: Benzenesulfonamides: a unique class of chemokine receptor type 4 inhibitors.
abstract: 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 in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC(50)=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.
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA. smooring@gsu.edu
authors.forename: Suazette Reid
authors.initials: SR
authors.lastname: Mooring
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ahn
authors.forename: Samuel
authors.initials: S
authors.lastname: Hong
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D054377:Chemokine CXCL12; D011725:Pyridines; D019718:Receptors, CXCR4; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C023666:pyridine