A chemical genomics screen highlights the essential role of mitochondria in HIF-1 regulation

Xiaoyu Lin, Caroline A. David, Jennifer B. Donnelly, Mike Michaelides, Navdeep S. Chandel, Xiaoli Huang, Usha Warrior, Frank Weinberg, Kathryn V. Tormos, Stephen W. Fesik, Yu Shen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


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-1α 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.

Original languageEnglish (US)
Pages (from-to)174-179
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - Jan 8 2008


  • Hypoxia
  • Hypoxia-inducible factor
  • RNAi
  • Reactive oxygen species
  • siRNA

ASJC Scopus subject areas

  • General

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