机构：[1]School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China,[2]Department of Pathology, Yunnan University of Chinese Medicine, Kunming, China,[3]XingYi People’ Hospital, Xingyi, China,[4]CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China,[5]Department of Physiology, Yunnan University of Chinese Medicine, Kunming, China,[6]Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, China,昆明医科大学附属第一医院[7]Department of the Second Medical Oncology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, China,[8]Department of Cadre Medical Branch, The Third Affiliated Hospital of Kunming Medical University, Kunming, China,[9]Department of Teaching and Research Section of Formulas of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, China,[10]School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine,Kunming, China,[11]Department of Computer Science and Engineering, Chinese University of Hong Kong, Hong Kong, China,[12]College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China,[13]Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,[14]Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States
Background: Hepatocellular carcinoma (HCC) is a lethal malignancy lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6) and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and are promising therapeutic targets for HCC. Here we identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC. Methods: Using a repurposing and ensemble docking methodology, we screened a library of worldwide approved drugs to identify candidate CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we investigated the effects of candidate drug in reducing cell-viability,inducing apoptosis, and causing cell-cycle arrest. The drug combination and thermal proteomic profiling (TPP) method were used to investigate whether the candidate drug produced antagonistic effect. The in vivo anti-cancer effect was performed in BALB/C nude mice subcutaneously xenografted with Huh7 cells. Results: We demonstrated for the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6 and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell viability, induced apoptosis, increased the percentage of cells in G1 phase. Drug combination screening indicated that aminoquinol could produce antagonistic effect with the PI3K inhibitor LY294002. TPP analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6, PI3K and AKT proteins. Finally, in vivo study in Huh7 cells xenografted nude mice demonstrated that aminoquinol exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil with the combination treatment showed the highest therapeutic effect. Conclusion: The present study indicates for the first time the discovery of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It could be used alone or as a combination therapeutic strategy for the treatment of HCC.
基金：
The present study was supported by grants from the Scientific
Research Fund Project of Department of Education of Yunnan
Province (No. 2017ZZX289, No. 2018JS208), Yunnan Applied
Basic Res of Combined Foundation of Yunnan Province Science
and Technology Dept. and Kunming Medical University Joint Fund
for Fundamental Research (2017FE467(-186), 2018FE001(-069),
2019FE001(-064)), Yunnan Applied Basic Res. of Combined
Foundation of Yunnan Province Science and Technology
Department, Yunnan University of Chinese Medicine (2018FF001
(-026), 2019FF002 (-050,-040), 2018FF001 (-016), 2018FF001
(-079)), and the National Natural Science Foundation of China
(No. 82060862, 81960835, No. 81802548, No. 81860451).
第一作者机构：[1]School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, China,
共同第一作者：
通讯作者：
通讯机构：[2]Department of Pathology, Yunnan University of Chinese Medicine, Kunming, China,[3]XingYi People’ Hospital, Xingyi, China,
推荐引用方式(GB/T 7714)：
Zhong-Kun Xia,Wei Wang,Jian-Ge Qiu,et al.Discovery of a New CDK4/6 and PI3K/AKT Multiple Kinase Inhibitor Aminoquinol for the Treatment of Hepatocellular Carcinoma[J].FRONTIERS IN PHARMACOLOGY.2021,12:doi:10.3389/fphar.2021.691769.
APA：
Zhong-Kun Xia,Wei Wang,Jian-Ge Qiu,Xi-Nan Shi,Hong-Jian Li...&Bing-Hua Jiang.(2021).Discovery of a New CDK4/6 and PI3K/AKT Multiple Kinase Inhibitor Aminoquinol for the Treatment of Hepatocellular Carcinoma.FRONTIERS IN PHARMACOLOGY,12,
MLA：
Zhong-Kun Xia,et al."Discovery of a New CDK4/6 and PI3K/AKT Multiple Kinase Inhibitor Aminoquinol for the Treatment of Hepatocellular Carcinoma".FRONTIERS IN PHARMACOLOGY 12.(2021)
