Engineered coiled-coil HIF1α protein domain mimic

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Targeted anti-cancer therapies aim for improved drug efficacy and diagnostics.
• Tumor microenvironment (TME) targeting offers a tumor-agnostic approach for universal agents.
• Hypoxia-inducible factor 1 (HIF1) is crucial for tumor adaptation to hypoxia; inhibiting its interaction with p300 shows therapeutic promise.

Purpose of the Study:

• To develop a novel therapeutic agent targeting the hypoxic tumor microenvironment.
• To create a multivalent assembled protein (MAP) based on HIF1α and cartilage oligomeric matrix protein (COMPcc).
• To assess the binding affinity, gene regulation, and in vivo targeting capabilities of the developed agent.

Main Methods:

• Utilized a multivalent assembled protein (MAP) strategy.
• Fused the COMPcc domain with critical residues of the HIF1α C-terminal transactivation domain (C-TAD).
• Generated HIF1α-MAP (H-MAP) and evaluated its binding affinity, gene downregulation, and in vivo tumor targeting.

Main Results:

• HIF1α-MAP (H-MAP) exhibited picomolar binding affinity to p300.
• The agent successfully downregulated hypoxia-inducible genes.
• H-MAP demonstrated effective in vivo tumor targeting capabilities.

Conclusions:

• HIF1α-MAP is a potent inhibitor of HIF1-p300 interaction.
• The developed agent shows promise as a universal tumor-targeting therapeutic.
• This approach leverages the hypoxic TME for targeted anti-cancer drug development.