BO-264: Highly potent TACC3 inhibitor as a novel anticancer drug candidate

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buir.advisorGöktuna, Serkan İsmail
dc.contributor.authorAkbulut, Özge
dc.date.accessioned2021-02-03T10:50:46Z
dc.date.available2021-02-03T10:50:46Z
dc.date.copyright2021-01
dc.date.issued2021-01
dc.date.submitted2021-02-01
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.descriptionCataloged from PDF version of article.en_US
dc.descriptionThesis (Ph.D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2021.en_US
dc.descriptionIncludes bibliographical references (leaves 124-143).en_US
dc.description.abstractBreast cancer has been consistently ranked to be the most common cancer and the second leading cause of cancer-related death in women worldwide for many years. Despite better understanding of tumor biology and the availability of plethora of anti-cancer therapeutics utilizing different strategies, complete response and/or long-term survival is achieved in only a small fraction of patients with aggressive disease. Since microtubule re-organization is an important step during cell division, drugs that interfere with this process have been a major focus of cancer research. Although anti-microtubule agents are widely used in clinic, cytotoxicity to non-tumorigenic cells and drug resistance are still the main obstacles. Therefore, development of alternative target molecules that selectively and efficiently target cancer cells, but restore normal cells are needed. Transforming acidic coiled-coil containing protein 3 (TACC3) is an important TACC family member, having both mitosis-related roles e.g. regulation of centrosomes and microtubule stability and interphase-related roles e.g. regulation of gene expression and cell migration. Being overexpressed in a broad spectrum of cancers and correlation of its expression with disease progression make TACC3 a highly attractive therapeutic target. Although the oncogenic role of TACC3 has been established albeit mostly in in vitro settings, there is currently no TACC3 inhibitor being tested in clinics. Therefore, by combining rational drug design and screening, we aimed to identify and characterize a novel TACC3 inhibitor hit molecule with high potency and minimum toxicity in in vitro and in vivo systems that is amenable for future drug development. BO-264 was identified as a novel inhibitor targeting TACC3 by direct binding validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. Compared to two other available TACC3 inhibitors, it showed superior inhibition of mitotic progression and cell viability, especially in aggressive basal and HER2+ breast cancer cell lines. Notably, BO-264 had remarkable cytotoxicity effect on several cancer cell lines in NCI-60 human cancer cell line panel (≥ 90% have less than 1 µM GI50 value) and inhibited the proliferation of FGFR3-TACC3 fusion protein-harboring cells, an oncogenic driver in several malignancies. Importantly, BO-264 did not cause any cytotoxicity to non-cancerous cell lines. Noteworthy, its oral administration significantly suppressed tumor growth in both breast and colon cancer syngeneic and xenograft models, and prolonged survival with no major toxicity. Finally, TACC3 expression level has been identified as a strong independent prognostic factor in breast cancer. Collectively, our preclinical findings suggest that BO-264 is a potent and non-toxic anti-cancer agent targeting TACC3 in breast and colon cancer and can be developed further to obtain better drug-like properties.en_US
dc.description.degreePh.D.en_US
dc.description.provenanceSubmitted by Betül Özen (ozen@bilkent.edu.tr) on 2021-02-03T10:50:46Z No. of bitstreams: 1 Ozge Akbulut_MBG_MFBE_January 2021.pdf: 13602685 bytes, checksum: 6ae7b9c8c941af9ef853d2b60e812674 (MD5)en
dc.description.provenanceMade available in DSpace on 2021-02-03T10:50:46Z (GMT). No. of bitstreams: 1 Ozge Akbulut_MBG_MFBE_January 2021.pdf: 13602685 bytes, checksum: 6ae7b9c8c941af9ef853d2b60e812674 (MD5) Previous issue date: 2021-02en
dc.description.statementofresponsibilityby Özge Akbuluten_US
dc.embargo.release2023-02-05
dc.format.extent165 leaves : color illustrations, charts ; 30 cm.en_US
dc.identifier.itemidB151654
dc.identifier.urihttp://hdl.handle.net/11693/54972
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBreast canceren_US
dc.subjectColon canceren_US
dc.subjectTargeted therapyen_US
dc.subjectTACC3en_US
dc.subjectInhibitoren_US
dc.subjectBO-264en_US
dc.subjectFGFR3-TACC3en_US
dc.titleBO-264: Highly potent TACC3 inhibitor as a novel anticancer drug candidateen_US
dc.title.alternativeBO-264: Özgün anti-kanser ilaç adayi olarak yüksek etki potansiyeline sahip TACC3 inhibitörüen_US
dc.typeThesisen_US

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