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

J Med Chem. 2019 Nov 27;62(22):10182-10203. doi: 10.1021/acs.jmedchem.9b01065. Epub 2019 Nov 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Binding, Competitive
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • DNA Topoisomerases, Type II / metabolism
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Epithelial-Mesenchymal Transition / drug effects*
  • Humans
  • Mice
  • Molecular Targeted Therapy
  • Poly-ADP-Ribose Binding Proteins / metabolism
  • Structure-Activity Relationship
  • TCF Transcription Factors / genetics*
  • TCF Transcription Factors / metabolism
  • Topoisomerase II Inhibitors / chemistry*
  • Topoisomerase II Inhibitors / pharmacokinetics
  • Topoisomerase II Inhibitors / pharmacology*
  • Transcription, Genetic


  • Poly-ADP-Ribose Binding Proteins
  • TCF Transcription Factors
  • Topoisomerase II Inhibitors
  • Adenosine Triphosphate
  • DNA Topoisomerases, Type II
  • TOP2A protein, human