Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution
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Jin-Xue He1,*, Meng Wang2,*, Xia-Juan Huan1, Chuan-Huizi Chen1, Shan-Shan Song1, Ying-Qing Wang1, Xue-Mei Liao1, Cun Tan2, Qian He2, Lin-Jiang Tong1, Yu-Ting Wang1, Xiao-Hua Li1, Yi Su1, Yan-Yan Shen1, Yi-Ming Sun1, Xin-Ying Yang1, Yi Chen1, Zhi-Wei Gao3, Xiao-Yan Chen3, Bing Xiong2, Xiu-Lian Lu4, Jian Ding1, Chun-Hao Yang2, Ze-Hong Miao1
1Division 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
2Department 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
3Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
4Cisen Pharmaceutical Co., LTD, Jining 272073, Shandong, China
*These authors contributed equally to this work
Ze-Hong Miao, email: firstname.lastname@example.org
Chun-Hao Yang, email: email@example.com
Keywords: MPH, PARP inhibitor, homologous recombination, antitumor activity, synthetic lethality
Received: April 01, 2016 Accepted: November 23, 2016 Published: December 01, 2016
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.
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