Natural Product-Based Inhibitors of Hypoxia-Inducible Factor-1 (HIF-1)

Author(s): Dale G. Nagle, Yu-Dong Zhou

Journal Name: Current Drug Targets

Volume 7 , Issue 3 , 2006

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Abstract:

The transcription factor hypoxia-inducible factor-1 (HIF-1) regulates the expression of more than 70 genes involved in cellular adaptation and survival under hypoxic stress. Activation of HIF-1 is associated with numerous physiological and pathological processes that include tumorigenesis, vascular remodeling, inflammation, and hypoxia/ischemiarelated tissue damage. Clinical studies suggested that HIF-1 activation correlates directly with advanced disease stages and treatment resistance among cancer patients. Preclinical studies support the inhibition of HIF-1 as a major molecular target for antitumor drug discovery. Considerable effort is underway, in government laboratories, industry and academia, to identify therapeutically useful small molecule HIF-1 inhibitors. Natural products (low molecular weight organic compounds produced by plants, microbes, and animals) continue to play a major role in modern antitumor drug discovery. Most of the compounds discovered to inhibit HIF-1 are natural products or synthetic compounds with structures that are based on natural product leads. Natural products have also served a vital role as molecular probes to elucidate the pathways that regulate HIF-1 activity. Natural products and natural product-derived compounds that inhibit HIF-1 are summarized in light of their biological source, chemical class, and effect on HIF-1 and HIF-mediated gene regulation. When known, the mechanism(s) of action of HIF-1 inhibitors are described. Many of the substances found to inhibit HIF-1 are non-druggable compounds that are too cytotoxic to serve as drug leads. The application of high-throughput screening methods, complementary molecular-targeted assays, and structurally diverse chemical libraries hold promise for the discovery of therapeutically useful HIF-1 inhibitors.

Keywords: HIF-1, Natural Product, Tumor Hypoxia, Molecular-Targeted Drug Discovery, Small Molecule HIF-1 Inhibitor, Hypoxia Selective

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Article Details

VOLUME: 7
ISSUE: 3
Year: 2006
Page: [355 - 369]
Pages: 15
DOI: 10.2174/138945006776054979
Price: $65

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