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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.
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