机构：[1]College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China[2]Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Individualized Medication Key Laboratory of Sichuan Province, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, School of Medicine, Center for Information in Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China四川省人民医院[3]Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China[4]Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan 610041, China四川大学华西医院[5]Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
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 mu M 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.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81703457, 81302643]; Sichuan Province People's Hospital Clinical Research and Transformation Fund key projects [2016LZ03]; National Key Specialty Construction Project of Clinical Pharmacy [30305030698, 202055031103]; Health Commission of Sichuan Province
第一作者机构：[1]College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China[5]Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Baowen Qi,Ling Zhong,Jun He,et al.Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents[J].JOURNAL OF MEDICINAL CHEMISTRY.2019,62(17):7697-7707.doi:10.1021/acs.jmedchem.9b00353.
APA：
Baowen Qi,Ling Zhong,Jun He,Hongjia Zhang,Fengqiong Li...&Jianyou Shi.(2019).Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents.JOURNAL OF MEDICINAL CHEMISTRY,62,(17)
MLA：
Baowen Qi,et al."Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents".JOURNAL OF MEDICINAL CHEMISTRY 62..17(2019):7697-7707
医学