Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy
文献类型：期刊论文
| 作者 | Chen, Wen-hua2; Song, Shan-shan3; Qi, Ming-hui1; Huan, Xia-juan3; Wang, Ying-qing3 ; Jiang, Hualiang2,4; Ding, Jian3; Ren, Guo-bin1; Miao, Ze-hong3; Li, Jian2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2017-11 |
| 卷号 | 38期号:11页码:1521-1532 |
| 关键词 | PARP-1 inhibitor olaparib breast cancer BRCA-deficient tumors |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2017.104 |
| 文献子类 | Article |
| 英文摘要 | Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50= 2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50= 3.2-37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40-510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 mu g/mL, 2652.5 mu g/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 mg.kg(-1).d(-1), for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 mg.kg(-1).d(-1), for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50= 6.64 mu mol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors. |
| WOS关键词 | PARP INHIBITORS ; MEDICINAL CHEMISTRY ; DRUG DISCOVERY ; CANCER ; THERAPY ; DESIGN ; FLUORINE ; SUCCESS ; PREDICT ; 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] ; "Shu Guang" project - 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 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6092088 |
| WOS记录号 | WOS:000414248600010 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272423]  |
| 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, Guo-bin; Miao, Ze-hong; 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, Shanghai Key Lab New Drug Design, Sch Pharm, Shanghai 200237, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Wen-hua,Song, Shan-shan,Qi, Ming-hui,et al. Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy[J]. ACTA PHARMACOLOGICA SINICA,2017,38(11):1521-1532. |
| APA | Chen, Wen-hua.,Song, Shan-shan.,Qi, Ming-hui.,Huan, Xia-juan.,Wang, Ying-qing.,...&Li, Jian.(2017).Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy.ACTA PHARMACOLOGICA SINICA,38(11),1521-1532. |
| MLA | Chen, Wen-hua,et al."Discovery of potent 2,4-difluoro-linker poly(ADP-ribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy".ACTA PHARMACOLOGICA SINICA 38.11(2017):1521-1532. |
入库方式： OAI收割
来源：上海药物研究所
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