Abstract
The hypoxia inducible factor (HIF) pathway has been considered to be an attractive anti-cancer target. One strategy to inhibit HIF activity is through the disruption of the HIF-1α–p300 protein-protein interaction. We report herein the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α–p300 interaction. We evaluated the effect of complex 1 on HIF-1α signaling pathway in vitro and in cellulo by using the dual luciferase reporter assay, co-immunoprecipitation assay, and immunoblot assay. Complex 1 exhibited a dose-dependent inhibition of HRE-driven luciferase activity, with an IC50 value of 1.22 μM. Complex 1 interfered with the HIF-1α–p300 interaction as revealed by a dose-dependent reduction of p300 co-precipitated with HIF-1α as the concentration of complex 1 was increased. Complex 1 repressed the phosphorylation of SRC, AKT and STAT3, and had no discernible effect on the activity of NF-κB. We anticipate that complex 1 could be utilized as a promising scaffold for the further development of more potent HIF-1α inhibitors for anti-cancer treatment.
Highlights
Physiological metabolism, cell proliferation and survival[12,13]
In this work we set out to investigate whether metal complexes could be used as inhibitors of the hypoxia inducible factor (HIF)-1α–p300 protein-protein interaction (PPI), for which no metal-based inhibitor has yet been reported in the literature
We screened five structurally diverse osmium(II) polypyridyl complexes against HIF-1αto see whether or not these scaffolds could potentially bind to the “hot spots” of the HIF-1α–p300 PPI and disrupt HIF-1αexpression[18]
Summary
Physiological metabolism, cell proliferation and survival[12,13]. Accumulating evidence has highlighted the role of HIF-1αand HIF-regulated gene products in tumorigenesis and metastasis[14]. The HIF-1αpathway has been considered to be an attractive anti-cancer target[15,16]. One strategy to inhibit HIF activity is through the disruption of the HIF-1α–p300 protein-protein interaction (PPI)[17,18]. To our knowledge, no metal-based HIF-1α–p300 PPI inhibitor has been reported yet in the literature. We report the identification of an osmium(II) complex as the first metal-based inhibitor of the HIF-1α–p300 interaction
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