Discovery of Inhibitors of Aurora/PLK Targets as Anticancer Agents

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

doi:10.1021/acs.jmedchem.9b00353

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. Epub 2019 Aug 21.

Authors

Baowen Qi^{1

2}, Ling Zhong^{3

4}, Jun He⁵, Hongjia Zhang³, Fengqiong Li³, Ting Wang³, Jing Zou³, Yao-Xin Lin², Chengchen Zhang³, Xiaoqiang Guo¹, Rui Li⁵, Jianyou Shi³

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Aurora Kinase A / antagonists & inhibitors
Aurora Kinase A / metabolism
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Female
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Polo-Like Kinase 1
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / metabolism
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tumor Cells, Cultured
Tumor Suppressor Proteins

Substances

Antineoplastic Agents
Cell Cycle Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Tumor Suppressor Proteins
PLK3 protein, human
PLK4 protein, human
PLK2 protein, human
AURKA protein, human
Aurora Kinase A
Protein Serine-Threonine Kinases
polo-like kinase 5, human