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Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-08-21 , DOI: 10.1021/acs.jmedchem.9b00353 Baowen Qi 1, 2 , Ling Zhong 3, 4 , Jun He 5 , Hongjia Zhang 3 , Fengqiong Li 3 , Ting Wang 3 , Jing Zou 3 , Yao-Xin Lin 2 , Chengchen Zhang 3 , Xiaoqiang Guo 1 , Rui Li 5 , Jianyou Shi 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-08-21 , DOI: 10.1021/acs.jmedchem.9b00353 Baowen Qi 1, 2 , Ling Zhong 3, 4 , Jun He 5 , Hongjia Zhang 3 , Fengqiong Li 3 , Ting Wang 3 , Jing Zou 3 , Yao-Xin Lin 2 , Chengchen Zhang 3 , Xiaoqiang Guo 1 , Rui Li 5 , Jianyou Shi 3
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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：
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。
更新日期：2019-08-05
中文翻译：
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。
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