Anticancer osmium complex inhibitors of the HIF-1α and p300 protein-protein interaction

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Molecular Oncology

Background:

• The hypoxia-inducible factor (HIF) pathway is a critical regulator of cellular response to low oxygen and is frequently dysregulated in cancer, making it an attractive therapeutic target.
• Inhibiting the interaction between HIF-1α and its co-activator p300 is a promising strategy to disrupt HIF pathway signaling and impede tumor growth.

Purpose of the Study:

• To identify and characterize the first metal-based inhibitor targeting the HIF-1α-p300 protein-protein interaction.
• To evaluate the efficacy of a novel osmium(II) complex (complex 1) in disrupting HIF-1α signaling in vitro and in cellulo.

Main Methods:

• Dual luciferase reporter assay to measure HRE-driven transcriptional activity.
• Co-immunoprecipitation assay to assess the interaction between HIF-1α and p300.
• Immunoblot assay to analyze the phosphorylation status of key signaling proteins (SRC, AKT, STAT3, NF-κB).

Main Results:

• Complex 1 demonstrated dose-dependent inhibition of HRE-driven luciferase activity with an IC50 of 1.22 μM.
• Co-immunoprecipitation confirmed that complex 1 dose-dependently disrupted the HIF-1α-p300 interaction.
• Complex 1 repressed the phosphorylation of SRC, AKT, and STAT3, while showing no effect on NF-κB activity.

Conclusions:

• Osmium(II) complex 1 represents the first metal-based inhibitor of the HIF-1α-p300 interaction.
• Complex 1 effectively inhibits HIF-1α signaling and downstream pathways relevant to cancer.
• This osmium(II) complex serves as a promising scaffold for developing novel HIF-1α inhibitors for anti-cancer drug discovery.