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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate

Ozge Akbulut, Deniz Lengerli, Ozge Saatci, Elif Duman, Urartu O.S. Seker, Aynur Isik, Aytekin Akyol, Burcu Caliskan, Erden Banoglu and Ozgur Sahin
Ozge Akbulut
1Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
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Deniz Lengerli
2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
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  • ORCID record for Deniz Lengerli
Ozge Saatci
1Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
3Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, South Carolina.
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Elif Duman
4UNAM-National Nanotechnology Research Center, Institute of Material Science and Nanotechnology, Bilkent University, Ankara, Turkey.
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Urartu O.S. Seker
4UNAM-National Nanotechnology Research Center, Institute of Material Science and Nanotechnology, Bilkent University, Ankara, Turkey.
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  • ORCID record for Urartu O.S. Seker
Aynur Isik
5Hacettepe University Transgenic Animal Technologies Research and Application Center, Ankara, Turkey.
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Aytekin Akyol
5Hacettepe University Transgenic Animal Technologies Research and Application Center, Ankara, Turkey.
6Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
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Burcu Caliskan
2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
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Erden Banoglu
2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
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  • ORCID record for Erden Banoglu
Ozgur Sahin
1Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
3Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, South Carolina.
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  • For correspondence: sahin@cop.sc.edu
DOI: 10.1158/1535-7163.MCT-19-0957 Published June 2020
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Abstract

TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint–dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 μmol/L GI50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3–TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1243–54

  • Received October 5, 2019.
  • Revision received February 11, 2020.
  • Accepted March 19, 2020.
  • Published first March 26, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (6)
June 2020
Volume 19, Issue 6
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A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate
Ozge Akbulut, Deniz Lengerli, Ozge Saatci, Elif Duman, Urartu O.S. Seker, Aynur Isik, Aytekin Akyol, Burcu Caliskan, Erden Banoglu and Ozgur Sahin
Mol Cancer Ther June 1 2020 (19) (6) 1243-1254; DOI: 10.1158/1535-7163.MCT-19-0957

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A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate
Ozge Akbulut, Deniz Lengerli, Ozge Saatci, Elif Duman, Urartu O.S. Seker, Aynur Isik, Aytekin Akyol, Burcu Caliskan, Erden Banoglu and Ozgur Sahin
Mol Cancer Ther June 1 2020 (19) (6) 1243-1254; DOI: 10.1158/1535-7163.MCT-19-0957
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Molecular Cancer Therapeutics
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