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Ref Type Journal Article
PMID (32217742)
Authors Akbulut O, Lengerli D, Saatci O, Duman E, Seker UOS, Isik A, Akyol A, Caliskan B, Banoglu E, Sahin O
Title A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate.
Journal Molecular cancer therapeutics
Vol
Issue
Date 2020 Mar 26
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
BO-264 BO264|BO 264 BO-264 is a small molecule drug that binds to and inhibits TACC3, which potentially induces mitotic arrest, increases DNA damage and apoptosis, and reduced cell viability, and inhibits tumor growth (PMID: 32217742).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 - TACC3 urinary bladder cancer sensitive BO-264 Preclinical - Cell culture Actionable In a preclinical study, BO-264 treatment inhibited Erk1/2 phosphorylation, induced mitotic arrest, and reduced viability of a urinary bladder cancer cell line harboring FGFR3-TACC3 in culture (PMID: 32217742). 32217742