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1: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):174-9. Epub 2008 Jan 2.
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A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation.

Lin X, David CA, Donnelly JB, Michaelides M, Chandel NS, Huang X, Warrior U, Weinberg F, Tormos KV, Fesik SW, Shen Y.

Cancer Research and Advanced Technology, Global Pharmaceutical Research and Development, AP10, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.

Hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development and progression by regulating genes that are vital for proliferation, glycolysis, angiogenesis, and metastasis. To identify strategies of targeting the HIF-1 pathway, we screened a siRNA library against the entire druggable genome and a small-molecule library consisting of 691,200 compounds using a HIF-1 reporter cell line. Although the siRNA library screen failed to reveal any druggable targets, the small-molecule library screen identified a class of alkyliminophenylacetate compounds that inhibit hypoxia-induced HIF-1 reporter activity at single-digit nanomolar concentrations. These compounds were found to inhibit hypoxia but not deferoxamine-induced HIF-1alpha protein stabilization. Further analysis indicated that the alkyliminophenylacetate compounds likely inhibit the HIF-1 pathway through blocking the hypoxia-induced mitochondrial reactive oxygen species (ROS) production. Strikingly, all of the nonalkyliminophenylacetate HIF-1 inhibitors identified from the small-molecule library screen were also found to target mitochondria like the alkyliminophenylacetate compounds. The exclusive enrichment of mitochondria inhibitors from a library of >600,000 diverse compounds by using the HIF-1 reporter assay highlights the essential role of mitochondria in HIF-1 regulation. These results also suggest that targeting mitochondrial ROS production might be a highly effective way of blocking HIF-1 activity in tumors.

Publication Types:
PMID: 18172210 [PubMed - indexed for MEDLINE]

PMCID: PMC2224181