title: Discovery of Novel CXCR2 Inhibitors Using Ligand-Based Pharmacophore Models.
abstract: The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer. Though the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents has been pursued by pharmaceutical companies within the past decade, there are currently no clinically approved CXCR2 inhibitors. A pharmacophore model based on previously reported CXCR2 antagonists was developed to screen a database of commercially available compounds. Small-molecule compounds identified from the pharmacophore screening were selected for in vitro screening in a cell-based CXCR2-mediated β-arrestin-2 recruitment assay and further characterized in several cell-based assays and lipopolysaccharide (LPS)-induced lung inflammation studies in mice. CX compounds identified from pharmacophore modeling inhibited cell migration, lung and colon cancer cell proliferation, and colony formation. Mechanistic studies of CX4152 showed that this compound inhibits CXCR2 signaling through downregulation of surface CXCR2. Additionally, CX4152 significantly inhibits CXCL8-mediated neutrophil migration and LPS-induced lung inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore model, we identified a novel set of sulfonamides from a diverse library of small molecules. These compounds inhibit CXCR2/β-arrestin-2 association, cell migration and proliferation, and acute inflammation in mouse models. CX compounds identified from our pharmacophore models are potential leads for further optimization and development as anti-inflammatory and anticancer agents.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Ha
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, and Translational Oncology Program, University of Michigan , North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
authors.forename: Bikash
authors.initials: B
authors.lastname: Debnath
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Odde
authors.affiliation: Department of Clinical Pharmacy, University of Southern California School of Pharmacy , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
authors.forename: Tim
authors.initials: T
authors.lastname: Bensman
authors.affiliation: Department of Clinical Pharmacy, University of Southern California School of Pharmacy , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
authors.forename: Henry
authors.initials: H
authors.lastname: Ho
authors.affiliation: Department of Clinical Pharmacy, University of Southern California School of Pharmacy , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Beringer
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, and Translational Oncology Program, University of Michigan , North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, Michigan 48109, United States.
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D019390:Arrestins / Q000276:immunology; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003412:Cricetulus; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000276:immunology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000893:Anti-Inflammatory Agents; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins