Aurora and polo-like kinases control the G2/M phase in cell mitosis, which are both considered as crucial targets for cancer cell proliferations. Here, naphthalene-based Aurora/PLK coinhibitors as leading compounds were designed through in silico approach, and a total of 36 derivatives were synthesized. One candidate (AAPK-25) was selected under in vitro cell based high throughput screening with an IC50 value = 0.4 μM to human colon cancer cell HCT-116. A kinome scan assay showed that AAPK-25 was remarkably selective to both Aurora and PLK families. The relevant genome pathways were also depicted by microarray based gene expression analysis. Furthermore, validated from a set of in vitro and in vivo studies, AAPK-25 significantly inhibited the development of the colon cancer growth and prolonged the median survival time at the end of the administration (p < 0.05). To sum up, AAPK-25 has a great potential to be developed for a chemotherapeutic agent in clinical use.

中文翻译：

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发现 Aurora/PLK 靶标抑制剂作为抗癌剂。


Aurora 和 Polo 样激酶控制细胞有丝分裂的 G2/M 期，这两者都被认为是癌细胞增殖的关键靶点。在此，通过计算机方法设计了以萘基 Aurora/PLK 共抑制剂为主导化合物，并合成了总共 36 种衍生物。在基于体外​​细胞的高通量筛选中选择了一种候选物 (AAPK-25)，其对人结肠癌细胞 HCT-116 的 IC50 值 = 0.4 μM。激酶组扫描分析表明，AAPK-25 对 Aurora 和 PLK 家族均具有显着选择性。还通过基于微阵列的基因表达分析描述了相关的基因组途径。此外，经过一系列体外和体内研究验证，AAPK-25 显着抑制结肠癌的生长，并延长给药结束时的中位生存时间 (p < 0.05)。综上所述，AAPK-25作为临床化疗药物具有巨大的开发潜力。