Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

doi:10.1016/j.canlet.2016.11.010

	Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials
	Yuan, Bo 1,2; Ye, Na 2,3; Song, Shan-Shan 1,2; Wang, Yu-Ting 1,2; Song, Zilan 2,3; Chen, Hua-Dong 1,2; Chen, Chuan-Huizi 1,2; Huan, Xia-Juan 1,2; Wang, Ying-Qing1,2 ; Su, Yi 1,2
刊名	CANCER LETTERS
	2017-02
卷号	386 页码:47-56
关键词	Homologous recombination repair defects Olaparib Growth inhibition Patient-derived xenografts Pharmacokinetics
ISSN号	0304-3835
DOI	10.1016/j.canlet.2016.11.010
文献子类	Article
英文摘要	Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26 to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[81573450] ; National Natural Science Foundation of China[81321092] ; National Basic Research Program of China[2015CB910603] ; Chinese Academy of Sciences (Hundred Talents Project)[XDA12020104] ; Institutes for Drug Discovery and Development of the Chinese Academy of Sciences[CASIMM0120152003] ; Institutes for Drug Discovery and Development of the Chinese Academy of Sciences[CASIMM0120153005] ; Science and Technology Commission of Shanghai Municipality[16JC1406300] ; Science and Technology Commission of Shanghai Municipality[14431905300] ; Science and Technology Commission of Shanghai Municipality[16XD1404600] ; State Key Laboratory of Drug Research[SIMM1601ZZ-03]
WOS关键词	OLAPARIB MAINTENANCE THERAPY ; BRCA MUTANT-CELLS ; DNA-REPAIR ; OVARIAN-CANCER ; HOMOLOGOUS RECOMBINATION ; POLYMERASE ; TUMORS ; PROLIFERATION ; MICROTUBULE
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000392773500005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275662]
专题	药物化学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药理学第一研究室
通讯作者	He, Jin-Xue; Zhang, Ao; Miao, Ze-Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Yuan, Bo,Ye, Na,Song, Shan-Shan,et al. Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials[J]. CANCER LETTERS,2017,386:47-56.
APA	Yuan, Bo.,Ye, Na.,Song, Shan-Shan.,Wang, Yu-Ting.,Song, Zilan.,...&Miao, Ze-Hong.(2017).Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials.CANCER LETTERS,386,47-56.
MLA	Yuan, Bo,et al."Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials".CANCER LETTERS 386(2017):47-56.