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Author Notes:

Correspondence: Erwin G Van Meir, Winship Cancer Institute, Emory University, 1365C Clifton Rd NE, Atlanta, GA 30322, USA; Tel: +1 404 7785563; Fax: +1 404 7785240; Email: evanmei@emory.edu and Binghe Wang, Department of Chemistry and Center for Biotechnology and Drug Discovery, Georgia State University, Atlanta, GA 30302-4098, USA; Tel.: +1 404 4135544; Fax: +1 404 4135543; Email: wang@gsu.edu

Authors' contributions: NSD and AAJ performed luciferase and Western blot assays.

CT screened the chemical library with the alkaline phosphatase assay.

RdN and KCN synthesized the chemical compounds.

SK generated the LN229-VEGF-Luc cells.

YL performed biostatistical analysis.

EGVM directed research and SK, SRM, BW and EGVM interpreted data and wrote the manuscript.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health (R01CA116804 to EGVM and R01CA46446-13 to KCN)) and an associated minority supplement (R01CA116804-S1 to SR), the Brain Tumor Foundation for Children, EmTechBio, the V Foundation, the University Research Committee of Emory University (to EGVM), and a fellowship from the Georgia State University Molecular Basis of Diseases Program (to SR).

Keywords:

  • drug development
  • cancer
  • transcription factor
  • hypoxia
  • angiogenesis
  • glycolysis

Sulfonamides as a New Scaffold for Hypoxia Inducible Factor Pathway Inhibitors

Tools:

Journal Title:

Bioorganic and Medicinal Chemistry Letters

Volume:

Volume 21, Number 18

Publisher:

, Pages 5528-5532

Type of Work:

Article | Post-print: After Peer Review

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 IC50 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.

Copyright information:

© 2011 Elsevier Ltd. All rights reserved

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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