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Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents

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posted on 21.08.2019, 17:08 by Baowen Qi, Ling Zhong, Jun He, Hongjia Zhang, Fengqiong Li, Ting Wang, Jing Zou, Yao-Xin Lin, Chengchen Zhang, Xiaoqiang Guo, Rui Li, Jianyou Shi
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.

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