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Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines

文献类型：期刊论文

作者Gao, Jing1,3; Zhou, Chen3; Zhong, Yan3,4; Shi, Li3; Luo, Xuanyang1,3,4; Su, Haixia1,4; Li, Minjun2; Xu, Yechun1,4; Zhang, Naixia3,4; Zhou, Hu1,3,4
刊名BIOCHEMICAL PHARMACOLOGY
出版日期2023
卷号207页码:16
关键词HSP90 ATP competitive inhibitors Tip-based affinity selection-mass spectrometry Dipyridamole Cell cycle regulators
ISSN号0006-2952
DOI10.1016/j.bcp.2022.115376
通讯作者Zhang, Naixia(nxzhang@simm.ac.cn) ; Zhou, Hu(zhouhu@simm.ac.cn)
英文摘要Molecular chaperone HSP90 has been considered as a promising target for anti-cancer drug development for years. However, due to the heat shock response induced by the ATP competitive inhibitors against HSP90, the therapeutic efficacies of the compounds are compromised, which consequently restricts the clinical use of HSP90-targeted inhibitors. Therefore, there is a need to discover novel HSP90-targeted modulators which exhibit acceptable inhibition activity against the chaperone and do not induce significant heat shock response in the meantime. Here in this study, we firstly developed a tip-based affinity selection-mass spectrometry platform with optimized experimental conditions/parameters for HSP90-targeted active compound screening, and then applied it to fish out inhibitors against HSP90 from a collection of 2,395 compounds composed of FDA-approved drugs and drug candidates. Dipyridamole, which acts as an anti-thrombotic agent by modulating multiple targets and has a long history of safe use, was identified to interact with HSP90 ' s N-terminal domain. The following con-ducted biophysical and biochemical experiments demonstrated that Dipyridamole could bind to HSP90 ' s ATP binding pocket and function as an ATP competitive inhibitor of the chaperone. Finally, cellular-based assays including CESTA, cell viability assessment and proteomic analysis etc. were performed to evaluate whether the interaction between HSP90 and Dipyridamole contributes to the anti-tumor effects of the compound. We then found that Dipyridamole inhibits the growth and proliferation of human cancer cells by downregulating cell cycle regulators and upregulating apoptotic cell signaling, which are potentially mediated by the binding of Dipyridamole to HSP90 and to PDEs (phosphodiesterases), respectively.
WOS关键词MOLECULAR CHAPERONE ; ONALESPIB AT13387 ; STRUCTURAL BASIS ; ATPASE ACTIVITY ; DOSE-ESCALATION ; PHASE-I ; INHIBITOR ; IDENTIFICATION ; ACTIVATION ; RESISTANCE
资助项目National Key Research and Development Program of China[2020YFA0509000] ; National Natural Science Foundation of China[32171220] ; National Natural Science Foundation of China[22107111] ; National Natural Science Foundation of China[31800693] ; Science and Technology Commission of Shanghai Municipality[20XD1424900] ; Shanghai Municipal Science and Technology Major Project ; Youth Innovation Promotion Association CAS[2022284]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000907563100001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/303917]  
专题新药研究国家重点实验室
通讯作者Zhang, Naixia; Zhou, Hu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Shanghai Adv Res Inst, Chinese Acad Sci, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Analyt Res Ctr Organ & Biol Mol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Gao, Jing,Zhou, Chen,Zhong, Yan,et al. Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines[J]. BIOCHEMICAL PHARMACOLOGY,2023,207:16.
APA Gao, Jing.,Zhou, Chen.,Zhong, Yan.,Shi, Li.,Luo, Xuanyang.,...&Zhou, Hu.(2023).Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines.BIOCHEMICAL PHARMACOLOGY,207,16.
MLA Gao, Jing,et al."Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines".BIOCHEMICAL PHARMACOLOGY 207(2023):16.

入库方式： OAI收割

来源：上海药物研究所

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