Drug Design Targeting T-Cell Factor-Driven Epithelial-Mesenchymal Transition as a Therapeutic Strategy for Colorectal...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Metastasis causes 90% of cancer mortality, with limited options for metastatic colorectal cancer (mCRC).
• T-cell factor (TCF) transcription drives colorectal cancer (CRC) and epithelial-mesenchymal transition (EMT), promoting metastasis and drug resistance.
• Current mCRC therapies offer only palliative care with low survival rates.

Purpose of the Study:

• To identify and develop novel therapeutic agents targeting topoisomerase IIα (TOP2A) for mCRC treatment.
• To investigate the role of TOP2A in TCF-driven transcription and its regulation of EMT in mCRC.
• To evaluate the efficacy and safety of TOP2A ATP-competitive inhibitors in preclinical models.

Main Methods:

• Design, synthesis, and biological evaluation of TOP2A ATP-competitive inhibitors.
• Assessment of TCF-transcription inhibition and EMT modulation in mCRC cells.
• In vitro and in vivo pharmacokinetic studies of the developed inhibitors.
• Comparison with existing TOP2A-targeting agents (poisons).

Main Results:

• Identified TOP2A as a crucial DNA-binding factor for TCF-transcription.
• Developed novel ATP-competitive inhibitors of TOP2A that prevent TCF-transcription.
• Demonstrated that these inhibitors modulate or reverse EMT in mCRC models.
• Showcased that inhibitors do not cause DNA damage, unlike TOP2A poisons.

Conclusions:

• Targeting TOP2A with ATP-competitive inhibitors presents a novel therapeutic strategy for mCRC.
• This approach offers a potentially safer alternative to TOP2A poisons by avoiding DNA damage.
• The findings suggest potential applications for these inhibitors in other cancer types driven by similar mechanisms.