neoamphimedine and Colorectal-Neoplasms

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.

Topics: Adenosine Triphosphate; Animals; Binding, Competitive; Cell Line, Tumor; Colorectal Neoplasms; DNA Topoisomerases, Type II; Drug Design; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Humans; Mice; Molecular Targeted Therapy; Poly-ADP-Ribose Binding Proteins; Structure-Activity Relationship; TCF Transcription Factors; Topoisomerase II Inhibitors; Transcription, Genetic