Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution
| Autor: | Chuan-Huizi Chen, Xiao-Yan Chen, Jin-Xue He, Yu-Ting Wang, Chunhao Yang, Meng Wang, Yi Su, Ze-Hong Miao, Yi Chen, Shanshan Song, Xinying Yang, Linjiang Tong, Cun Tan, Jian Ding, Zhi-Wei Gao, Yiming Sun, Qian He, Bing Xiong, Xiao-hua Li, Huan Xiajuan, Xiu-Lian Lu, Xue-mei Liao, Yanyan Shen, Ying-Qing Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell Survival homologous recombination Antineoplastic Agents Synthetic lethality Pharmacology Poly(ADP-ribose) Polymerase Inhibitors Poly (ADP-Ribose) Polymerase Inhibitor Heterocyclic Compounds 4 or More Rings 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine PARP1 Pharmacokinetics In vivo Cell Line Tumor Neoplasms Temozolomide Medicine Animals Humans antitumor activity Tissue Distribution Cell Proliferation business.industry Drug Synergism Cell Cycle Checkpoints Haplorhini Xenograft Model Antitumor Assays synthetic lethality Rats Dacarbazine 030104 developmental biology PARP inhibitor Oncology chemistry 030220 oncology & carcinogenesis Cancer cell MPH Growth inhibition business Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Jin-Xue He 1, * , Meng Wang 2, * , Xia-Juan Huan 1 , Chuan-Huizi Chen 1 , Shan-Shan Song 1 , Ying-Qing Wang 1 , Xue-Mei Liao 1 , Cun Tan 2 , Qian He 2 , Lin-Jiang Tong 1 , Yu-Ting Wang 1 , Xiao-Hua Li 1 , Yi Su 1 , Yan-Yan Shen 1 , Yi-Ming Sun 1 , Xin-Ying Yang 1 , Yi Chen 1 , Zhi-Wei Gao 3 , Xiao-Yan Chen 3 , Bing Xiong 2 , Xiu-Lian Lu 4 , Jian Ding 1 , Chun-Hao Yang 2 , Ze-Hong Miao 1 1 Division of Anti-Tumor Pharmacology and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, University of Chinese Academy of Sciences, Beijing 100049, China 2 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, University of Chinese Academy of Sciences, Beijing 100049, China 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China 4 Cisen Pharmaceutical Co., LTD, Jining 272073, Shandong, China * These authors contributed equally to this work Correspondence to: Ze-Hong Miao, email: zhmiao@simm.ac.cn Chun-Hao Yang, email: chyang@simm.ac.cn Keywords: MPH, PARP inhibitor, homologous recombination, antitumor activity, synthetic lethality Received: April 01, 2016 Accepted: November 23, 2016 Published: December 01, 2016 ABSTRACT 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 γH2AX 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 γH2AX 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. |
| Databáze: | OpenAIRE |
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