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

Journal of medicinal chemistry 2019 Nov 27

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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.

Citation

Adedoyin D Abraham, Hector Esquer, Qiong Zhou, Nicholas Tomlinson, Brayden D Hamill, Joshua M Abbott, Linfeng Li, Laura A Pike, Sébastien Rinaldetti, Dominique A Ramirez, Paul J Lunghofer, Jose D Gomez, Jerome Schaack, Travis Nemkov, Angelo D'Alessandro, Kirk C Hansen, Daniel L Gustafson, Wells A Messersmith, Daniel V LaBarbera. Drug Design Targeting T-Cell Factor-Driven Epithelial-Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer. Journal of medicinal chemistry. 2019 Nov 27;62(22):10182-10203