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

Metastasis is the cause of 90% of mortality in cancer
patients.
For metastatic colorectal cancer (mCRC), the standard-of-care drug
therapies only palliate the symptoms but are ineffective, evidenced
by a low survival rate of ∼11%. T-cell factor (TCF) transcription
is a major driving force in CRC, and we have characterized it to be
a master regulator of epithelial–mesenchymal transition (EMT).
EMT transforms relatively benign epithelial tumor cells into quasi-mesenchymal
or mesenchymal cells that possess cancer stem cell properties, promoting
multidrug resistance and metastasis. We have identified topoisomerase
IIα (TOP2A) as a DNA-binding factor required for TCF-transcription.
Herein, we describe the design, synthesis, biological evaluation,
and in vitro and in vivo pharmacokinetic analysis of TOP2A ATP-competitive
inhibitors that prevent TCF-transcription and modulate or reverse
EMT in mCRC. Unlike TOP2A poisons, ATP-competitive inhibitors do not
damage DNA, potentially limiting adverse effects. This work demonstrates
a new therapeutic strategy targeting TOP2A for the treatment of mCRC
and potentially other types of cancers.