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A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate.
Akbulut, Ozge; Lengerli, Deniz; Saatci, Ozge; Duman, Elif; Seker, Urartu O S; Isik, Aynur; Akyol, Aytekin; Caliskan, Burcu; Banoglu, Erden; Sahin, Ozgur.
Afiliação
  • Akbulut O; Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
  • Lengerli D; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
  • Saatci O; Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
  • Duman E; Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, South Carolina.
  • Seker UOS; UNAM-National Nanotechnology Research Center, Institute of Material Science and Nanotechnology, Bilkent University, Ankara, Turkey.
  • Isik A; UNAM-National Nanotechnology Research Center, Institute of Material Science and Nanotechnology, Bilkent University, Ankara, Turkey.
  • Akyol A; Hacettepe University Transgenic Animal Technologies Research and Application Center, Ankara, Turkey.
  • Caliskan B; Hacettepe University Transgenic Animal Technologies Research and Application Center, Ankara, Turkey.
  • Banoglu E; Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
  • Sahin O; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Mol Cancer Ther ; 19(6): 1243-1254, 2020 06.
Article em En | MEDLINE | ID: mdl-32217742
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Biomarcadores Tumorais / Regulação Neoplásica da Expressão Gênica / Neoplasias do Colo / Proteínas Associadas aos Microtúbulos / Mitose / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Biomarcadores Tumorais / Regulação Neoplásica da Expressão Gênica / Neoplasias do Colo / Proteínas Associadas aos Microtúbulos / Mitose / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Ano de publicação: 2020 Tipo de documento: Article