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Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation

文献类型：期刊论文

作者Zhu, Shulei1; Shen, Qianqian2; Gao, Yinglei2; Wang, Lei1; Fang, Yanfen2; Chen, Yi2; Lu, Wei1
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-05-28
卷号63期号:10页码:5421-5441
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c00305
通讯作者Fang, Yanfen(yffang@simm.ac.cn) ; Lu, Wei(wlu@chem.ecnu.edu.cn)
英文摘要Herein, a series of HSP90 inhibitor-SN38 conjugates through ester and carbamate linkage in the 20-OH and 10-OH positions of SN38 were developed for improving the tumor-specific penetration and accumulation of SN38 via extracellular HSP90 (eHSP90)-mediated endocytosis. Mechanistic analyses confirmed that these novel conjugates could bind to eHSP90 and be selectively internalized into the tumor cells, which led to prolonged tumor regression in multiple models of cancer. Among all studied conjugates, compound 18b showed excellent in vitro activities, including acceptable HSP90 alpha affinity and potent antitumor activity. Moreover, compound 18b exhibited superior antitumor activity and low toxicity in HCT116 and Capan-1 xenograft models. Pharmacokinetic analyses in HCT116 and Capan-1 xenografts further confirmed that compound 18b treatment could lead to effective cleavage and extended SN38 exposure at tumor sites. All these encouraging data indicate that this compound is a promising new candidate for cancer therapy and merits further chemical and biological evaluation.
WOS关键词SHOCK-PROTEIN 90 ; TOPOISOMERASE-I ; EXTRACELLULAR HSP90 ; CAMPTOTHECIN PRODRUG ; THERAPEUTIC AGENTS ; DUAL INHIBITORS ; DELIVERY ; SN38
资助项目China Postdoctoral Science Foundation[2019M651435]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000585210700025
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/292530]  
专题新药研究国家重点实验室
通讯作者Fang, Yanfen; Lu, Wei
作者单位1.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, Shanghai 200062, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Shulei,Shen, Qianqian,Gao, Yinglei,et al. Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(10):5421-5441.
APA Zhu, Shulei.,Shen, Qianqian.,Gao, Yinglei.,Wang, Lei.,Fang, Yanfen.,...&Lu, Wei.(2020).Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation.JOURNAL OF MEDICINAL CHEMISTRY,63(10),5421-5441.
MLA Zhu, Shulei,et al."Design, Synthesis, and Biological Evaluation of HSP90 Inhibitor-SN38 Conjugates for Targeted Drug Accumulation".JOURNAL OF MEDICINAL CHEMISTRY 63.10(2020):5421-5441.

入库方式： OAI收割

来源：上海药物研究所

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