Show simple item record

dc.contributor.authorAkbulut, Özge
dc.contributor.authorLengerli, D.
dc.contributor.authorSaatci, Özge
dc.contributor.authorDuman, Elif
dc.contributor.authorŞeker, Urartu Özgür Şafak
dc.contributor.authorIşık, A.
dc.contributor.authorAkyol, A.
dc.contributor.authorÇalışkan, B.
dc.contributor.authorBanoğlu, E.
dc.contributor.authorŞahin, Özgür
dc.date.accessioned2021-03-04T08:41:02Z
dc.date.available2021-03-04T08:41:02Z
dc.date.issued2020
dc.identifier.issn1538-8514
dc.identifier.urihttp://hdl.handle.net/11693/75771
dc.description.abstractTACC3, 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.en_US
dc.language.isoEnglishen_US
dc.source.titleMolecular cancer therapeuticsen_US
dc.relation.isversionofhttps://dx.doi.org/10.1158/1535-7163.MCT-19-0957en_US
dc.titleA highly potent TACC3 inhibitor as a novel anticancer drug candidateen_US
dc.typeArticleen_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.departmentInstitute of Materials Science and Nanotechnology (UNAM)en_US
dc.departmentNanotechnology Research Center (NANOTAM)en_US
dc.citation.spage1243en_US
dc.citation.epage1254en_US
dc.citation.volumeNumber19en_US
dc.citation.issueNumber6en_US
dc.identifier.doi10.1158/1535-7163.MCT-19-0957en_US
dc.publisherNLM (Medline)en_US
dc.contributor.bilkentauthorAkbulut, Özge
dc.contributor.bilkentauthorSaatci, Özge
dc.contributor.bilkentauthorDuman, Elif
dc.contributor.bilkentauthorŞeker, Urartu Özgür Şafak
dc.contributor.bilkentauthorŞahin, Özgür


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record