中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells

文献类型:期刊论文

作者Qu, Bingxue1,3; Xu, Yongjin3; Lu, Yang1; Zhuang, Weihao1; Jin, Xinxin1; Shi, Qiuqiu1; Yan, Shike1; Guo, Yu1; Shen, Zheyuan4; Che, Jinxin1,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-05-05
卷号235
ISSN号0223-5234
关键词XPO1 Multiple myeloma MM.1S N-phenylsulfonamide Oral administration
DOI10.1016/j.ejmech.2022.114257
通讯作者Dong, Xiaowu(dongxw@zju.edu.cn) ; Yang, Haiyan(yanghy@zjcc.org.cn)
英文摘要Multiple myeloma (MM) is a highly malignant hematologic cancer that occurs when an atypical plasma cell develops in the bone marrow and reproduces quickly. Despite varies of new drugs have been developed or under clinic trial, MM is still essentially incurable, while XPO1 inhibition has emerged as a promising therapeutic strategy in the treatment of MM. Using the second-generation XPO1 inhibitor KPT-8602 as the lead compound, structure-based optimization provided D4 with high anti-proliferation efficacy (IC50 =& nbsp;24 nM in MM.1S). In addition, the treatment with D4 significantly induced MM.1S cell cycle arrested and cell apoptosis, which was confirmed as on-target effect by immunofluorescence microscopy and competitive binding assay. Moreover, D4 displayed good metabolic stability over rat plasma and liver microsomes, as well as good pharmacokinetic profile on SD rat model with high drug exposure and decent bioavailability by oral gavage. All these good properties of D4 pave the way for further drug development and clinical application. (C)& nbsp;2022 Elsevier Masson SAS. All rights reserved.
WOS关键词NUCLEAR EXPORT SINE ; SELECTIVE INHIBITORS ; THERAPEUTIC TARGET ; DRUG-METABOLISM ; TRANSPORT
资助项目National Natural Science Foundation of China[82173660] ; National Natural Science Foundation of China[82103975] ; Natural Science Foundation of Zhejiang Province[LR21H300003] ; Natural Science Foundation of Zhejiang Province[LQ21H300005] ; Natural Science Foundation of Zhejiang Province[Q22H302109]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:000793692700002
资助机构National Natural Science Foundation of China ; Natural Science Foundation of Zhejiang Province
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/130951]  
专题中国科学院合肥物质科学研究院
通讯作者Dong, Xiaowu; Yang, Haiyan
作者单位1.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou, Peoples R China
2.Zhejiang Univ, Canc Ctr, Hangzhou, Peoples R China
3.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Univ Chinese Acad Sci, Zhejiang Canc Hosp,Canc Hosp,Dept Lymphoma, Hangzhou, Peoples R China
4.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714
Qu, Bingxue,Xu, Yongjin,Lu, Yang,et al. Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,235.
APA Qu, Bingxue.,Xu, Yongjin.,Lu, Yang.,Zhuang, Weihao.,Jin, Xinxin.,...&Yang, Haiyan.(2022).Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,235.
MLA Qu, Bingxue,et al."Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 235(2022).

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来源:合肥物质科学研究院

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