title: Sulfonamides as a new scaffold for hypoxia inducible factor pathway inhibitors.
abstract: Solid tumors generally grow under hypoxic conditions, a pathophysiological change, which activates the expression of genes responsible for malignant, aggressive, and treatment-refractory properties. Hypoxia inducible factor (HIF) is the chief transcription factor regulating hypoxia-driven gene expression. Therefore, the HIF pathway has become a critical target for cancer therapeutics development. We screened a privileged library of about 10,000 natural-product-like compounds using a cell-based assay for HIF-dependent transcriptional activity and identified several arylsulfonamide HIF pathway inhibitors. Among these compounds, the most potent ones showed an IC(50) of ∼0.5 μM in the hypoxia-responsive element (HRE)-luciferase reporter system. Further studies are needed to fully elucidate the mechanism of action of this class of compounds and their structure-activity relationship.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Chalet
authors.initials: C
authors.lastname: Tan
authors.forename: Rita G
authors.initials: RG
authors.lastname: de Noronha
authors.forename: Narra S
authors.initials: NS
authors.lastname: Devi
authors.forename: Adnan A
authors.initials: AA
authors.lastname: Jabbar
authors.forename: Stefan
authors.initials: S
authors.lastname: Kaluz
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Suazette Reid
authors.initials: SR
authors.lastname: Mooring
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Binghe
authors.initials: B
authors.lastname: Wang
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D015394:Molecular Structure; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D054852:Small Molecule Libraries; D013449:Sulfonamides; D014157:Transcription Factors; D000469:Alkaline Phosphatase