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Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells

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资源类型：
Pubmed体系：
作者：
Pan Zhaoping[1] * ; Chen Yi[2] * ; Pang Haiying[1] ; Wang Xiaoyun[1] ; Zhang Yuehua[1] ; Xie Xin[3] ; He Gu[1,4,*1] ;
机构： [1]Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China [2]Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China [3]College of Medical Technology and School of Pharmacy, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China [4]Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China
出处：
DOI： 10.1016/j.ejmech.2022.114674
ISSN：

关键词： Hsp90 mTOR Dual inhibitor Bladder cancer Autophagy

摘要：
In this study, a novel class of thieno [2,3-d] pyrimidine derivatives containing resorcinol and morpholine fragments as Hsp90/mTOR dual inhibitors was designed, synthesized, and evaluated. In vitro anti-tumor assay results: the obtained compounds demonstrated effectiveness in suppressing the enzymatic activities of the Hsp90 and mTOR and inhibiting the proliferation of J82, T24, and SW780 cancer cell lines. Among these dual inhibitors, the most potent compound 17o, confirmed remarkable inhibitory activities on Hsp90, mTOR, and SW780 cell. Furthermore, the molecular dynamics simulation and a panel of mechanism studies revealed that inhibitor 17o suppressed the proliferation of SW780 cells through the over-activation of the PI3K/AKT/mTOR pathway regulated by mTOR inhibition and apoptosis regulated by the mitochondrial pathway. In subcutaneous J82 xenograft models, the compound 17o also presented considerable in vivo anti-tumor activity. Therefore, our investigations highlight that a new-found dual Hsp90/mTOR inhibitor by rational drug design strategies could be a promising lead compound for targeted bladder cancer therapy and deserves further studies.Copyright © 2022 Elsevier Masson SAS. All rights reserved.

基金：
This work was supported by grants from National Natural Science Foundation of China (Grant No. 22177084, 81872535 and 82073471) and the Fundamental Research Funds for the Science & Technology department of Sichuan Province (Grant Nos. 2022YFQ0054, 2019YFSY0038 and 2020YFH0036) and the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21036).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类 | 1 区 医学
小类 | 1 区 药物化学
最新[2023]版：
大类 | 2 区 医学
小类 | 1 区 药物化学
第一作者：
第一作者机构： [1]Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China [4]Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China [*1]Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
推荐引用方式(GB/T 7714)：
Pan Zhaoping,Chen Yi,Pang Haiying,et al.Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells[J].European journal of medicinal chemistry.2022,242:114674.doi:10.1016/j.ejmech.2022.114674.
APA：
Pan Zhaoping,Chen Yi,Pang Haiying,Wang Xiaoyun,Zhang Yuehua...&He Gu.(2022).Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells.European journal of medicinal chemistry,242,
MLA：
Pan Zhaoping,et al."Design, synthesis, and biological evaluation of novel dual inhibitors of heat shock protein 90/mammalian target of rapamycin (Hsp90/mTOR) against bladder cancer cells".European journal of medicinal chemistry 242.(2022):114674

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