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.
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- Target identification
- Mechanism of action
- Small molecules
- Target validation
Welsh, S. J., Dale, A. G., Lombardo, C. M., Valentine, H., de la Fuente, M., Schatzlein, A., & Neidle, S. (2013). Inhibition of the hypoxia-inducible factor pathway by a G-quadruplex binding small molecule. Scientific Reports, 3, 1-9. https://doi.org/10.1038/srep02799