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Methods Enzymol. 2007;435:385-402.

Hypoxia-inducible factor 1 inhibitors.

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Developmental Therapeutics Program, SAIC Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, USA.


The tremendous progress in our understanding of the molecular mechanisms underlying the presence and consequences of hypoxia in human cancers has been accompanied by renewed enthusiasm for the development of therapeutic strategies targeting hypoxic cells signaling pathways. Hypoxia-inducible factor 1 (HIF-1), a key transcriptional activator that mediates hypoxic responses, has been the focus of intense investigation and efforts to identify small molecule inhibitors or novel strategies for HIF-1 inhibition have multiplied over the last few years. Despite challenges associated with targeting transcription factors, which hamper these efforts, several strategies have been pursued. In this chapter, protocols related to screening assays, both cell-based and cell-free, are described and discussed in the context of their application for the identification of HIF-1 inhibitors. While cell-based assays offer the opportunity to reveal unidentified components of the hypoxic cell signaling pathway, cell-free targeted approaches may lead to the identification of more selective HIF-1 inhibitors. Validation of "hits" and characterization of their mechanism of action are essential for a rational development of putative HIF-1 inhibitors in preclinical models and early clinical trials.

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