基于结构设计的新型mTOR抑制剂的抗宫颈癌活性研究

doi:10.5246/jcps.2020.09.056

中国药学(英文版) ›› 2020, Vol. 29 ›› Issue (9): 603-616.DOI: 10.5246/jcps.2020.09.056

• 【研究论文】 • 下一篇

基于结构设计的新型mTOR抑制剂的抗宫颈癌活性研究

焦佩丽^1#, 李奕言^1#, 吴兴², 王昱曦¹, 毛蓓蓓³, 金宏威¹, 张礼和¹, 张亮仁^1*, 刘振明^1*

1. 北京大学医学部药学院天然药物及仿生药物国家重点实验室, 北京 100191
2. 横店集团控股有限公司, 浙江 310007
3. 山东中医药大学药学院, 山东济南 250355

收稿日期:2020-05-30 修回日期:2020-06-27 出版日期:2020-09-30 发布日期:2020-07-11
通讯作者: Tel.: +86-10-82802567; +86-10-82805281; Fax: +86-10-82802724
基金资助:
National Natural Science Foundation of China (Grant No. 21772005, 81872730) and the Beijing Natural Science Foundation (Grant No. 7202088, 7172118).

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

Peili Jiao^1#, Yiyan Li^1#, Xing Wu², Yuxi Wang¹, Beibei Mao³, Hongwei Jin¹, Lihe Zhang¹, Liangren Zhang^1*, Zhenming Liu^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).

摘要/Abstract

摘要：

激酶mTOR是PI3K-AKT信号通路的关键组成部分, 该激酶在宫颈癌细胞中被高度激活。本文运用基于结构的药物发现等手段发现了一系列mTOR激酶抑制剂并对其进行生物学评价, 发现其可发挥有效的抗宫颈癌作用。酶活性测定结果显示化合物C3具有潜在的mTOR抑制作用(IC₅₀ = 1.57 μM)。随后利用分子对接和动力学模拟探究并预测mTOR激酶和C3的结合模式,初步探讨了化合物的构效关系。在多种肿瘤细胞系上进行细胞增殖活性实验时发现,C3对宫颈癌细胞HeLa表现出较好的增殖抑制活性(IC₅₀ = 0.38 μM)。此外,C3还能浓度依赖性地降低磷酸化核糖体S6 (p-S6)蛋白在HeLa细胞内的表达水平。值得注意的是,C3发挥显著的抗宫颈癌活性很有可能是mTOR通路和其他细胞内通路的共同作用。本研究表明C3可进一步开发为宫颈癌的治疗药物。

关键词: 基于结构的药物发现, mTOR抑制剂, 分子模拟, 细胞内通路, 宫颈癌

Abstract:

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

中图分类号:

R916.1

Supporting:

焦佩丽, 李奕言, 吴兴, 王昱曦, 毛蓓蓓, 金宏威, 张礼和, 张亮仁, 刘振明. 基于结构设计的新型mTOR抑制剂的抗宫颈癌活性研究[J]. 中国药学(英文版), 2020, 29(9): 603-616.

Peili Jiao, Yiyan Li, Xing Wu, Yuxi Wang, Beibei Mao, Hongwei Jin, Lihe Zhang, Liangren Zhang, Zhenming Liu. Structure-based design and biological evaluation of novel mTOR inhibitors as potential anti-cervical agents[J]. Journal of Chinese Pharmaceutical Sciences, 2020, 29(9): 603-616.

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基于结构设计的新型mTOR抑制剂的抗宫颈癌活性研究

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

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