discoveryofpotent24difluorolinkerpolyadpribosepolymerase1inhibitorswithenhancedwatersolubilityandinvivoanticancerefficacy

doi:10.1038/aps.2017.104

	discoveryofpotent24difluorolinkerpolyadpribosepolymerase1inhibitorswithenhancedwatersolubilityandinvivoanticancerefficacy
	Chen Wenhua 1; Song Shanshan 2; Ql Minghui 1; Huan Xiajuan 2; Wang Yingqing 2; Jiang Hualiang 1; Ding Jian 2; Ren Guobin 1; Miao Zehong 2; Li Jian 1
刊名	actapharmacologicasinica
	2017
卷号	38 期号:11 页码:1521
关键词	PARP INHIBITORS MEDICINAL CHEMISTRY DRUG DISCOVERY CANCER THERAPY DESIGN FLUORINE SUCCESS PREDICT METRICS PARP-1 inhibitor olaparib breast cancer BRCA-deficient tumors
ISSN号	1671-4083
DOI	10.1038/aps.2017.104
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.
资助项目	[National Natural Science Foundation of China] ; ["Shu Guang" Project - Shanghai Municipal Education Commission] ; [Shanghai Education Development Foundation] ; [Science and Technology Commission of Shanghai Municipality] ; [Fundamental Research Funds for the Central Universities]
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/283377]
专题	中国科学院上海药物研究所
作者单位	1.华东理工大学 2.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Chen Wenhua,Song Shanshan,Ql Minghui,et al. discoveryofpotent24difluorolinkerpolyadpribosepolymerase1inhibitorswithenhancedwatersolubilityandinvivoanticancerefficacy[J]. actapharmacologicasinica,2017,38(11):1521.
APA	Chen Wenhua.,Song Shanshan.,Ql Minghui.,Huan Xiajuan.,Wang Yingqing.,...&Li Jian.(2017).discoveryofpotent24difluorolinkerpolyadpribosepolymerase1inhibitorswithenhancedwatersolubilityandinvivoanticancerefficacy.actapharmacologicasinica,38(11),1521.
MLA	Chen Wenhua,et al."discoveryofpotent24difluorolinkerpolyadpribosepolymerase1inhibitorswithenhancedwatersolubilityandinvivoanticancerefficacy".actapharmacologicasinica 38.11(2017):1521.