Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells

doi:10.1016/j.ejmech.2022.114257

	Design, synthesis and biological evaluation of sulfonamides inhibitors of XPO1 displaying activity against multiple myeloma cells
	Qu, Bingxue 1,2; Xu, Yongjin 1; Lu, Yang 2; Zhuang, Weihao 2; Jin, Xinxin 2; Shi, Qiuqiu 2; Yan, Shike 2; Guo, Yu 2; Shen, Zheyuan 3; Che, Jinxin 2,3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2022-05-05
卷号	235
关键词	XPO1 Multiple myeloma MM.1S N-phenylsulfonamide Oral administration
ISSN号	0223-5234
DOI	10.1016/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.
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关键词	NUCLEAR EXPORT SINE ; SELECTIVE INHIBITORS ; THERAPEUTIC TARGET ; DRUG-METABOLISM ; TRANSPORT
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
内容类型	期刊论文
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.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Univ Chinese Acad Sci, Zhejiang Canc Hosp,Canc Hosp,Dept Lymphoma, Hangzhou, Peoples R China 2.Zhejiang Univ, Coll Pharmaceut Sci, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou, Peoples R China 3.Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou, Peoples R China 4.Zhejiang Univ, Canc Ctr, 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).