Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials

doi:10.1111/cas.13947

	Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials
	Wang, Lei 2; Yang, Changyong 1,3,4,5; Xie, Chengying 2; Jiang, Jiahua 3; Gao, Mingzhao 2; Fu, Li 2; Li, Yun 2; Bao, Xubin 2; Fu, Haoyu 2; Lou, Liguang 2
刊名	CANCER SCIENCE
	2019-03-01
卷号	110 期号:3 页码:1064-1075
关键词	antitumor activity fluzoparib pharmacokinetics poly(ADP-ribose) polymerase toxicity
ISSN号	1347-9032
DOI	10.1111/cas.13947
通讯作者	Lou, Liguang(lglou@mail.shcnc.ac.cn)
英文摘要	Poly(ADP-ribose) polymerase (PARP) enzymes play an important role in repairing DNA damage and maintaining genomic stability. Olaparib, the first-in-class PARP inhibitor, has shown remarkable clinical benefits in the treatment of BRCA-mutated ovarian or breast cancer. However, the undesirable hematological toxicity and pharmacokinetic properties of olaparib limit its clinical application. Here, we report the first preclinical characterization of fluzoparib (code name: SHR-3162), a novel, potent, and orally available inhibitor of PARP. Fluzoparib potently inhibited PARP1 enzyme activity and induced DNA double-strand breaks, G(2)/M arrest, and apoptosis in homologous recombination repair (HR)-deficient cells. Fluzoparib preferentially inhibited the proliferation of HR-deficient cells and sensitized both HR-deficient and HR-proficient cells to cytotoxic drugs. Notably, fluzoparib showed good pharmacokinetic properties, favorable toxicity profile, and superior antitumor activity in HR-deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved antitumor responses without extra toxicity. Based on these findings, studies to evaluate the efficacy and safety of fluzoparib (phase II) and those two combinations (phase I) have been initiated. Taken together, our results implicate fluzoparib as a novel attractive PARP inhibitor.
资助项目	National Natural Science Foundation of China[81502636] ; Yunnan Provincial Science and Technology Department[2017ZF010] ; Science and Technology Commission of Shanghai Municipality[14DZ2294100]
WOS关键词	PARP INHIBITORS ; DOUBLE-BLIND ; HOMOLOGOUS RECOMBINATION ; MAINTENANCE THERAPY ; DOWN-REGULATION ; OVARIAN-CANCER ; COMBINATION ; OLAPARIB ; TUMORS ; AGENTS
WOS研究方向	Oncology
语种	英语
出版者	WILEY
WOS记录号	WOS:000460316200021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290384]
专题	中国科学院上海药物研究所
通讯作者	Lou, Liguang
作者单位	1.Southeast Univ, Sch Chem & Chem Engn, Nanjing, Jiangsu, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 3.Jiangsu Hengrui Med Co Ltd, Lianyungang, Peoples R China 4.Southeast Univ, Pharmaceut Res Ctr, Nanjing, Jiangsu, Peoples R China 5.Southeast Univ, Jiangsu Prov Hitech Key Lab Biomed Res, Nanjing, Jiangsu, Peoples R China
推荐引用方式 GB/T 7714	Wang, Lei,Yang, Changyong,Xie, Chengying,et al. Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials[J]. CANCER SCIENCE,2019,110(3):1064-1075.
APA	Wang, Lei.,Yang, Changyong.,Xie, Chengying.,Jiang, Jiahua.,Gao, Mingzhao.,...&Lou, Liguang.(2019).Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials.CANCER SCIENCE,110(3),1064-1075.
MLA	Wang, Lei,et al."Pharmacologic characterization of fluzoparib, a novel poly(ADP-ribose) polymerase inhibitor undergoing clinical trials".CANCER SCIENCE 110.3(2019):1064-1075.