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Identification of a Novel Small-Molecule Inhibitor of the Hypoxia-Inducible Factor 1 Pathway

Departments of ¹ Neurosurgery and ² Hematology-Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia; ³ Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute and ⁴ Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California; ⁵ REQUIMTE/CQFB, Chemistry Department, FCT, Universidade Nova de Lisboa, Caparica, Portugal; and ⁶ Department of Chemistry, University of Georgia, Athens, Georgia

Requests for reprints: Erwin G. Van Meir, Laboratory of Molecular Neuro-Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road, Atlanta, GA 30322. Phone: 404-778-5563; Fax: 404-778-5550; E-mail: evanmei{at}emory.edu.

Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library. The compounds of the library, which share a 2,2-dimethylbenzopyran structural motif, were tested for their ability to inhibit the hypoxic activation of an alkaline phosphatase reporter gene under the control of hypoxia-responsive elements in human glioma cells. This effort led to the discovery of 103D5R, a novel small-molecule inhibitor of HIF-1. 103D5R markedly decreased HIF-1 protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner, whereas minimally affecting global cellular protein expression levels, including that of control proteins such as HIF-1ß, IB, and ß-actin. The inhibitory activity of 103D5R against HIF-1 was clearly shown under normoxia and hypoxia in cells derived from different cancer types, including glioma, prostate, and breast cancers. This inhibition prevented the activation of HIF-1 target genes under hypoxia such as vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). Investigations into the molecular mechanism showed that 103D5R strongly reduced HIF-1 protein synthesis, whereas HIF-1 mRNA levels and HIF-1 degradation were not affected. 103D5R inhibited the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH₂-kinase, without changing the total levels of these proteins. Further studies on the mechanism of action of 103D5R will likely provide new insights into its validity/applicability for the pharmacologic targeting of HIF-1 for therapeutic purposes.

Key Words: hypoxia-inducible factor 1 (HIF-1) • combinatorial library • protein degradation • protein synthesis • tumor angiogenesis

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