Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule

Sarah J. Welsh, Aaron G. Dale, Caterina M. Lombardo, Helen Valentine, Maria de la Fuente, Andreas Schatzlein, Stephen Neidle

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29 Citations (Scopus)
30 Downloads (Pure)


The hypoxia-inducible transcription factor (HIF) co-ordinates the response of tumours to low oxygen by stimulating genes involved in metabolism and angiogenesis. HIF pathway activation is associated with decreased progression-free survival and increased mortality; compounds that target this pathway are potential agents for the treatment of a range of solid tumour malignancies. Renal cancers are likely to be particularly sensitive to inhibition of the HIF pathway since ∼80% show constitutive activation of HIF. We have previously described the di-substituted naphthalene derivative, CL67, which binds to a G-quadruplex higher-order structure in the HIF promoter sequence in vitro. We show here that CL67 blocks HIF expression leading to inhibition of HIF-transactivation and down-regulation of downstream target genes and proteins in renal carcinoma cell lines and in a mouse xenograft model of renal cancer. This inhibition is independent of pathways that control HIF abundance through oxygen-dependant degradation and oxygen dependant HIF sub-unit expression.
Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalScientific Reports
Publication statusPublished - 2013
Externally publishedYes

Bibliographical note

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  • Target identification
  • Mechanism of action
  • Small molecules
  • Target validation


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