Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents

  • J Med Chem. 2019 Sep 12;62(17):7697-7707. 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
Affiliations
  • 1. College of Pharmacy and Biological Engineering , Chengdu University , Chengdu 610106 , China.
  • 2. Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 3. 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.
  • 4. Chengdu Institute of Biology , Chinese Academy of Sciences , Chengdu 610041 , China.
  • 5. Cancer Center, West China Hospital , Sichuan University, and Collaborative Innovation Center for Biotherapy , Sichuan 610041 , China.
PMID: 31381325 DOI: 10.1021/acs.jmedchem.9b00353
Abstract

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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