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.

中文翻译：

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作为新型抗癌候选药物的高效 TACC3 抑制剂

TACC3 是一种转化酸性卷曲螺旋 (TACC) 家族成员，在包括乳腺癌在内的多种癌症中经常上调。它在保护癌症中经常失调的微管稳定性和中心体完整性方面发挥着关键作用；因此，使 TACC3 成为极具吸引力的治疗靶点。在这里，我们通过内部化合物收集的筛选确定了一种新的 TACC3 靶向化学型 BO-264。BO-264 和 TACC3 之间的直接相互作用通过使用多种生化方法得到验证，包括药物亲和力响应目标稳定性、细胞热位移测定和等温滴定量热法。BO-264 表现出优于目前报道的两种 TACC3 抑制剂的抗增殖活性，尤其是在侵袭性乳腺癌亚型、基础型和 HER2+ 中，通过纺锤体组装检查点依赖性有丝分裂停滞、DNA 损伤和细胞凋亡，而对正常乳腺细胞的细胞毒性可以忽略不计。此外，BO-264 在有丝分裂和间期期间显着降低中心体 TACC3。BO-264 在危害九种不同癌症类型的 NCI-60 细胞系面板中显示出有效的抗增殖活性（~90% 的 GI50 值小于 1 μmol/L）。值得注意的是，BO-264 显着抑制了携带 FGFR3-TACC3 融合细胞的生长，FGFR3-TACC3 融合是多种恶性肿瘤的致癌驱动因素。重要的是，它的口服给药显着损害了免疫功能低下和免疫功能正常的乳腺癌和结肠癌小鼠模型的肿瘤生长，并在没有任何主要毒性的情况下增加了存活率。最后，TACC3 表达已被确定为乳腺癌的强独立预后因素，并在几种不同的癌症中具有强预后作用。总体而言，我们确定了一种新型且高效的 TACC3 抑制剂作为新型潜在抗癌剂，可诱导纺锤体异常和有丝分裂细胞死亡。