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Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution

文献类型：期刊论文

作者He, Jin-Xue1,2,3; Wang, Meng3,4; Huan, Xia-Juan1,2,3; Chen, Chuan-Huizi1,2,3; Song, Shan-Shan1,2,3; Wang, Ying-Qing1,2,3; Liao, Xue-Mei1,2,3; Tan, Cun3,4; He, Qian3,4; Tong, Lin-Jiang1,2,3
刊名ONCOTARGET
出版日期2017-01-17
卷号8期号:3页码:4156-4168
关键词MPH PARP inhibitor homologous recombination antitumor activity synthetic lethality
ISSN号1949-2553
DOI10.18632/oncotarget.13749
文献子类Article
英文摘要The approval of poly(ADP-ribose) polymerase (PARP) inhibitor AZD2281 in 2014 marked the successful establishment of the therapeutic strategy targeting homologous recombination repair defects of cancers in the clinic. However, AZD2281 has poor water solubility, low tissue distribution and relatively weak in vivo anticancer activity, which appears to become limiting factors for its clinical use. In this study, we found that mefuparib hydrochloride (MPH) was a potent PARP inhibitor, possessing prominent in vitro and in vivo anticancer activity. Notably, MPH displayed high water solubility (> 35 mg/ml) and potent PARP1/2 inhibition in a substrate-competitive manner. It reduced poly(ADP-ribose) (PAR) formation, enhanced.H2AX levels, induced G2/M arrest and subsequent apoptosis in homologous recombination repair (HR)-deficient cells. Proof-of-concept studies confirmed the MPH-caused synthetic lethality. MPH showed potent in vitro and in vivo proliferation and growth inhibition against HR-deficient cancer cells and synergistic sensitization of HR-proficient xenografts to the anticancer drug temozolomide. A good relationship between the anticancer activity and the PARP inhibition of MPH suggested that PAR formation and.H2AX accumulation could serve as its pharmacodynamic biomarkers. Its high bioavailability (40%+/- 100%) and high tissue distribution in both monkeys and rats were its most important pharmacokinetic features. Its average concentrations were 33-fold higher in the tissues than in the plasma in rats. Our work supports the further clinical development of MPH as a novel PARP1/2 inhibitor for cancer therapy.
WOS关键词DNA-DAMAGE RESPONSE ; POLY(ADP-RIBOSE) POLYMERASE-1 ; THERAPEUTIC OPPORTUNITIES ; CANCER ; PROLIFERATION ; TUMORS
资助项目National Natural Science Foundation of China[21072205] ; National Natural Science Foundation of China[81573450] ; National Natural Science Foundation of China[81373446] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81603160] ; National Natural Science Foundation of China[81402961] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2012ZX09103101-071] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2014ZX09102001-007] ; Chinese Academy of Sciences[XDA12020205] ; Chinese Academy of Sciences[CASIMM0120152003] ; Chinese Academy of Sciences[CASIMM0120153005] ; Science and Technology Commission of Shanghai Municipality[16JC1406300] ; State Key Laboratory of Drug Research[SIMM1601ZZ-03]
WOS研究方向Oncology ; Cell Biology
语种英语
WOS记录号WOS:000393228400033
出版者IMPACT JOURNALS LLC
源URL[http://119.78.100.183/handle/2S10ELR8/275672]  
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Yang, Chun-Hao; Miao, Ze-Hong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Med Chem, Shanghai 201203, Peoples R China;
5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
6.Cisen Pharmaceut Co LTD, Jining 272073, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 He, Jin-Xue,Wang, Meng,Huan, Xia-Juan,et al. Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution[J]. ONCOTARGET,2017,8(3):4156-4168.
APA He, Jin-Xue.,Wang, Meng.,Huan, Xia-Juan.,Chen, Chuan-Huizi.,Song, Shan-Shan.,...&Miao, Ze-Hong.(2017).Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution.ONCOTARGET,8(3),4156-4168.
MLA He, Jin-Xue,et al."Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution".ONCOTARGET 8.3(2017):4156-4168.

入库方式： OAI收割

来源：上海药物研究所

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