Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy

doi:10.1016/j.ejmech.2017.06.053

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	Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy
	Chen, Wenhua 2; Guo, Ne 3,4; Qi, Minghui 1; Dai, Haiying 2; Hong, Minghuang 1; Guan, Longfei 2; Huan, Xiajuan 3; Song, Shanshan 3; He, Jinxue 3; Wang, Yingqing3
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2017-09-29
卷号	138 页码:514-531
关键词	Antitumor drug BRCA1/2 PARP inhibitors Molecular docking
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2017.06.053
文献子类	Article
英文摘要	Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARPI inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 13 nM), V-C8 cells (IC50 = 0.003 nM), Capan-1 cells (IC50 = 7.1 nM) and MDA-MB-436 cells (IC50 = 0.2 nM). Compound 47 had more potent PARPI-DNA trapping and double-strand breaks (DSBs)-induction activities than 1 and induced G2/M arrest and caspase-dependent apoptosis. Compound 47 (50 mg/kg, 94.2%) had a more beneficial effect on tumor growth inhibition than 1 (100 mg/kg, 65.0%) in a BRCA1-mutated xenograft model and significantly inhibited tumor growth (40 mg/kg, 48.1%) in a BRCA2-mutated xenograft model, with no negative influence on the body weight of the mice. Collectively, these data demonstrated that 47 might be an excellent drug candidate for the treatment of cancer, especially for BRCA-deficient tumors. (C) 2017 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[21672064] ; National Natural Science Foundation of China[8152200403] ; National Natural Science Foundation of China[21372001] ; Shanghai Municipal Education Commission[00000000] ; Shanghai Education Development Foundation[14SG28] ; Science and Technology Commission of Shanghai Municipality[15431901200] ; Fundamental Research Funds for the Central Universities[00000000]
WOS关键词	POLY(ADP-RIBOSE) POLYMERASE PARP ; MEDICINAL CHEMISTRY ; ANTICANCER ACTIVITY ; DRUG DISCOVERY ; DNA ; FLUORINE ; DESIGN ; ABT-888 ; SUCCESS ; METRICS
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:000411297000041
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272475]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Ren, Guobin; Miao, Zehong; Li, Jian
作者单位	1.East China Univ Sci & Technol, Sch Pharm, Lab Pharmaceut Crystal Engn & Technol, Shanghai 200237, Peoples R China; 2.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Chen, Wenhua,Guo, Ne,Qi, Minghui,et al. Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,138:514-531.
APA	Chen, Wenhua.,Guo, Ne.,Qi, Minghui.,Dai, Haiying.,Hong, Minghuang.,...&Li, Jian.(2017).Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,138,514-531.
MLA	Chen, Wenhua,et al."Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 138(2017):514-531.