Regulating the ARNT/TACC3 axis: multiple approaches to manipulating protein/protein interactions with small molecules

Area of Science:

• Molecular Biology
• Biochemistry
• Drug Discovery

Background:

• Developing small molecule inhibitors for protein/protein complexes, especially transcription factors, is challenging but crucial for disease intervention.
• Misregulation of transcription factor complexes is linked to various diseases.

Purpose of the Study:

• To identify small molecule regulators targeting the hypoxia signaling transcription factor complex involving HIF and TACC3.
• To explore parallel strategies for discovering protein/protein interaction inhibitors.

Main Methods:

• In vitro NMR and biochemical screening to identify ARNT binders.
• Cell-based screening to identify inhibitors of TACC3 signaling.
• Characterization of small molecules KG-548 and KHS101.

Main Results:

• KG-548 was identified as a direct disruptor of the ARNT/TACC3 interaction by binding to the ARNT PAS domain.
• KHS101 was shown to indirectly inhibit HIF complex formation by destabilizing TACC3 and HIF-1α.
• Parallel screening approaches yielded distinct regulators of the HIF complex.

Conclusions:

• Small molecule regulators for the HIF/TACC3 complex were successfully identified.
• Parallel strategies are effective for developing inhibitors of challenging protein/protein interactions.
• These findings offer potential therapeutic avenues for diseases associated with HIF pathway dysregulation.