Journal of Chinese Pharmaceutical Sciences ›› 2020, Vol. 29 ›› Issue (9): 603-616.DOI: 10.5246/jcps.2020.09.056

• Original articles •     Next Articles

Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents

Peili Jiao1#, Yiyan Li1#, Xing Wu2, Yuxi Wang1, Beibei Mao3, Hongwei Jin1, Lihe Zhang1, Liangren Zhang1*, Zhenming Liu1*   

  1. 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
    2. Hengdian Group Holdings Limited, Zhejiang 310007, China
    3. College of Pharmaceutical Science, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
  • Received:2020-05-30 Revised:2020-06-27 Online:2020-09-30 Published:2020-07-11
  • Contact: Tel.: +86-10-82802567; +86-10-82805281; Fax: +86-10-82802724
  • Supported by:
    National Natural Science Foundation of China (Grant No. 21772005, 81872730) and the Beijing Natural Science Foundation (Grant No. 7202088, 7172118).


The mammalian target of rapamycin (mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of mTOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential mTOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell HeLa (IC50 = 0.38 μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein (p-S6) in HeLa cells in a dose-dependent manner. Noteworthily, mTOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.

Key words: Structure-based drug discovery, mTOR inhibitors, Molecular modeling, Cellular pathway, Cervical cancer

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