Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors

doi:10.1016/j.ejmech.2021.113333

	Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors
	Gao, Dingding 1,3; Jin, Nan 2; Fu, Yixian 2,4; Zhu, Yueyue 1; Wang, Yujie 1; Wang, Ting 2; Chen, Yuehong 2; Zhang, Mingming 1; Xiao, Qiang 1; Huang, Min 2,4
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2021-04-15
卷号	216 页码:20
关键词	STAT3 signaling pathway Benzothiazole Rational design Antitumor activity Molecular docking
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2021.113333
通讯作者	Li, Yingxia(liyx417@fudan.edu.cn)
英文摘要	The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated. Of note, compound B19 demonstrated excellent activity against IL-6/STAT3 signaling pathway with the IC50 value as low as 0.067 mu M as determined by a luciferase reporter assay. Moreover, multiple compounds displayed potent antiproliferative activity against MDA-MB-468 and JAK2 mutant HEL cell lines. Further biochemical study using Western blot assay indicated that B19 blocked the phosphorylation of STAT3 at Tyr 705 and Ser 727 and thus suppressed STAT3-mediated gene expression of c-MYC and MCL-1. Simultaneously, it induced cancer cell G2/M phase arrest and apoptosis both in MDA-MB-468 and HEL cell lines. Finally, molecular docking study along with surface plasmon resonance (SPR) and fluorescence polarization (FP) assays disclosed the binding mode of B19 in STAT3 SH2 domain. Taken together, our finding suggests that B19 is a promising therapeutic STAT3 inhibitor for cancer treatment. (C) 2021 Elsevier Masson SAS. All rights reserved.
资助项目	Significant New Drugs Development[2018ZX09711002-003-009] ; National Natural Science Foundation of China[81973178] ; National Natural Science Foundation of China[U1906212]
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:000637742700032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/296636]
专题	中国科学院上海药物研究所
通讯作者	Li, Yingxia
作者单位	1.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med IRI, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Gao, Dingding,Jin, Nan,Fu, Yixian,et al. Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,216:20.
APA	Gao, Dingding.,Jin, Nan.,Fu, Yixian.,Zhu, Yueyue.,Wang, Yujie.,...&Li, Yingxia.(2021).Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,216,20.
MLA	Gao, Dingding,et al."Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 216(2021):20.