文献类型：期刊文献

中文题名：Discovery of potent 2,4-difluoro-linker poly（ADPribose） polymerase i inhibitors with enhanced water solubility and in vivo anticancer efficacy

英文题名：Discovery of potent 2,4-difluoro-linker poly（ADPribose） polymerase i inhibitors with enhanced water solubility and in vivo anticancer efficacy

作者：Wen-hua CHEN[1];Shan-shan SONG[2];Ming-hui QI[3];Xia-juan HUAN[2];Ying-qing WANG[2];Hualiang JIANG[2,4];Jian DING[2];Guo-bin REN[3];Ze-hong MIAO[2];Jian LI[1]

机构：[1]Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;[2]Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;[3]Laboratory of Pharmaceutical Crystal Engineering & Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;[4]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

年份：2017

卷号：38

期号：11

起止页码：1521

中文期刊名：Acta Pharmacologica Sinica

外文期刊名：中国药理学报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2017_2018】；PubMed;

基金：Financial support of this research was provided by the National Natural Science Foundation of China （Grants 21672064, 8152200403 and 21372001）, the ＂Shu Guang＂ Project supported by the Shanghai Municipal Education Commission and the Shanghai Education Development Foundation （Grant 14SG28）, the Science and Technology Commission of Shanghai Municipality （No 15431901200）, and the Fundamental Research Funds for the Central Universities.

语种：英文

中文关键词：PARP-1 inhibitor; olaparib; breast cancer; BRCA-deficient tumors

外文关键词：PARP-1 inhibitor; olaparib; breast cancer; BRCA-deficient tumors

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 3.7, 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 （S1=40-510）. The corresponding hydrochloride salts 56 and 57 （based on 43 and 47） were highly water soluble in pH=l.0 buffered salt solutions （1628.2 μg/mL, 2652.5 μg/mL）. In a BRCAl-mutated xenograft model, oral administration of compound 56 （30 mg.kg 1.d1, 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·k-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 （ICso=6.64 pmol/L）. Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.
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 3.7, 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 （S1=40-510）. The corresponding hydrochloride salts 56 and 57 （based on 43 and 47） were highly water soluble in pH=l.0 buffered salt solutions （1628.2 μg/mL, 2652.5 μg/mL）. In a BRCAl-mutated xenograft model, oral administration of compound 56 （30 mg.kg 1.d1, 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·k-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 （ICso=6.64 pmol/L）. Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.