title: Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution.
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.
authors.affiliation: 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.
authors.forename: Jin-Xue
authors.initials: JX
authors.lastname: He
authors.affiliation: 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.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xia-Juan
authors.initials: XJ
authors.lastname: Huan
authors.affiliation: 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.
authors.forename: Chuan-Huizi
authors.initials: CH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Ying-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Liao
authors.affiliation: 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.
authors.forename: Cun
authors.initials: C
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: He
authors.affiliation: 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.
authors.forename: Lin-Jiang
authors.initials: LJ
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Xin-Ying
authors.initials: XY
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Gao
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Cisen Pharmaceutical Co., LTD, Jining 272073, Shandong, China.
authors.forename: Xiu-Lian
authors.initials: XL
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D000882:Haplorhini; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D000077204:Temozolomide; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C000626298:mefuparib hydrochloride; D003606:Dacarbazine; D000077204:Temozolomide
keywords: MPH; PARP inhibitor; antitumor activity; homologous recombination; synthetic lethality