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Novel PARP1/2 inhibitor mefuparib hydrochloride elicits potent in vitro and in vivo anticancer activity, characteristic of high tissue distribution.
He, Jin-Xue; Wang, Meng; Huan, Xia-Juan; Chen, Chuan-Huizi; Song, Shan-Shan; Wang, Ying-Qing; Liao, Xue-Mei; Tan, Cun; He, Qian; Tong, Lin-Jiang; Wang, Yu-Ting; Li, Xiao-Hua; Su, Yi; Shen, Yan-Yan; Sun, Yi-Ming; Yang, Xin-Ying; Chen, Yi; Gao, Zhi-Wei; Chen, Xiao-Yan; Xiong, Bing; Lu, Xiu-Lian; Ding, Jian; Yang, Chun-Hao; Miao, Ze-Hong.
Affiliation
  • He JX; 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.
  • Wang M; 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.
  • Huan XJ; 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.
  • Chen CH; 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.
  • Song SS; 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.
  • Wang YQ; 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.
  • Liao XM; 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.
  • Tan C; 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.
  • He Q; 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.
  • Tong LJ; 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.
  • Wang YT; 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.
  • Li XH; 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.
  • Su Y; 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.
  • Shen YY; 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.
  • Sun YM; 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.
  • Yang XY; 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.
  • Chen Y; 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.
  • Gao ZW; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Chen XY; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • Xiong B; 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.
  • Lu XL; Cisen Pharmaceutical Co., LTD, Jining 272073, Shandong, China.
  • Ding J; 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.
  • Yang CH; 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.
  • Miao ZH; 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.
Oncotarget ; 8(3): 4156-4168, 2017 Jan 17.
Article in En | MEDLINE | ID: mdl-27926532
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Poly(ADP-ribose) Polymerase Inhibitors / Heterocyclic Compounds, 4 or More Rings / Neoplasms / Antineoplastic Agents Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Oncotarget Year: 2017 Document type: Article Affiliation country:
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Poly(ADP-ribose) Polymerase Inhibitors / Heterocyclic Compounds, 4 or More Rings / Neoplasms / Antineoplastic Agents Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Oncotarget Year: 2017 Document type: Article Affiliation country: