2. Academic Validation
  3. Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials

  • Cancer Lett. 2017 Feb 1;386:47-56. doi: 10.1016/j.canlet.2016.11.010.
Bo Yuan 1,  Na Ye 2,  Shan-Shan Song 1,  Yu-Ting Wang 1,  Zilan Song 2,  Hua-Dong Chen 1,  Chuan-Huizi Chen 1,  Xia-Juan Huan 1,  Ying-Qing Wang 1,  Yi Su 1,  Yan-Yan Shen 1,  Yi-Ming Sun 1,  Xin-Ying Yang 1,  Yi Chen 1,  Shi-Yan Guo 3,  Yong Gan 3,  Zhi-Wei Gao 3,  Xiao-Yan Chen 3,  Jian Ding 1,  Jin-Xue He 4,  Ao Zhang 5,  Ze-Hong Miao 6
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China.
  • 2 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China; Department of Medicinal Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China. Electronic address: jxhe@simm.ac.cn.
  • 5 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China; Department of Medicinal Chemistry, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: aozhang@simm.ac.cn.
  • 6 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, China. Electronic address: zhmiao@simm.ac.cn.
PMID: 27847302 DOI: 10.1016/j.canlet.2016.11.010
Abstract

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective Anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical Anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and Apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient Cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional Anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient Cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human Cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib.

Keywords

Growth inhibition; Homologous recombination repair defects; Olaparib; Patient-derived xenografts; Pharmacokinetics.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-115552
    99.51%, PARP1/2抑制剂
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