Discovery, mechanism and metabolism studies of 2,3-difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy
文献类型：期刊论文
| 作者 | Chen, Wenhua2; Guo, Ne3,4; Qi, Minghui1; Dai, Haiying2; Hong, Minghuang1; Guan, Longfei2; Huan, Xiajuan3; Song, Shanshan3; He, Jinxue3; Wang, Yingqing3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 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. |
| WOS关键词 | POLY(ADP-RIBOSE) POLYMERASE PARP ; MEDICINAL CHEMISTRY ; ANTICANCER ACTIVITY ; DRUG DISCOVERY ; DNA ; FLUORINE ; DESIGN ; ABT-888 ; SUCCESS ; METRICS |
| 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研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000411297000041 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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