Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. Mol Cancer Ther; 16(11); 2410–21. ©2017 AACR .

中文翻译：

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使用新的抑制剂化合物靶向TAO激酶可延缓有丝分裂并诱导中心体扩增乳腺癌细胞中的有丝分裂细胞死亡。

一千个氨基酸激酶（TAOK）1和2在有丝分裂过程中被催化激活，并可能有助于有丝分裂细胞的圆化和纺锤体定位。在这里，我们表征了一种抑制TAOK1和TAOK2活性的化合物，其IC50值为11至15 nmol / L，具有ATP竞争性，并选择性地靶向这些激酶。在中心体扩增的SKBR3或BT549乳腺癌细胞模型中，TAOK抑制或耗竭增加了有丝分裂群体，显示有扩增的中心体和多极纺锤体的有丝分裂细胞的百分比，诱导了细胞死亡，并抑制了细胞生长。相反，非致瘤性和分裂性双极MCF-10A乳腺细胞似乎对TAOK活性的依赖性较小，并且可以在有TAOK抑制剂的情况下完成有丝分裂并增殖。我们证明有丝分裂期间TAOK1和TAOK2分别位于细胞质和中心体。活细胞成像显示TAOK抑制剂延长了SKBR3细胞的有丝分裂持续时间，增加了有丝分裂细胞的死亡，并降低了离开有丝分裂的细胞的百分比，而MCF-10A细胞则继续分裂和增殖。超过80％的乳腺癌组织显示出多余的中心体，肿瘤细胞经常聚集多余的中心体，以避免多极有丝分裂和相关的细胞死亡。因此，刺激中心体去簇并诱导多极的药物可能优先靶向分裂中心体扩增的癌细胞，同时保留正常的双极细胞。我们的研究结果表明TAOK抑制作用可增强癌细胞中的中心体消簇和有丝分裂灾难，这些蛋白质因此可能提供适用于药物抑制和可能发生多余中心体的乳腺癌潜在治疗的新型治疗靶点。分子癌疗法；16（11）; 2410–21。©2017 AACR。