Open AccessDrug Design Targeting T-Cell Factor-Driven Epithelial–Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer
Author(s) -
Adedoyin D. Abraham,
Hector Esquer,
Qiong Zhou,
Nicholas Tomlinson,
Brayden D. Hamill,
Joshua M. Abbott,
Linfeng Li,
Laura A. Pike,
Sébastien Rinaldetti,
Dominique 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
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01065
Subject(s) - colorectal cancer , epithelial–mesenchymal transition , cancer research , metastasis , mesenchymal stem cell , in vivo , transcription factor , chemistry , cancer , cancer cell , pharmacology , medicine , biology , pathology , biochemistry , gene , microbiology and biotechnology
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.