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

Bo Yuan, Na Ye, Shan Shan Song, Yu Ting Wang, Zilan Song, Hua Dong Chen, Chuan Huizi Chen, Xia Juan Huan, Ying Qing Wang, Yi Su, Yan Yan Shen, Yi Ming Sun, Xin Ying Yang, Yi Chen, Shi Yan Guo, Yong Gan, Zhi Wei Gao, Xiao Yan Chen, Jian Ding, Jin Xue HeAo Zhang, Ze Hong Miao

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)47-56
Number of pages10
JournalCancer Letters
Volume386
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yuan, B., Ye, N., Song, S. S., Wang, Y. T., Song, Z., Chen, H. D., Chen, C. H., Huan, X. J., Wang, Y. Q., Su, Y., Shen, Y. Y., Sun, Y. M., Yang, X. Y., Chen, Y., Guo, S. Y., Gan, Y., Gao, Z. W., Chen, X. Y., Ding, J., ... Miao, Z. H. (2017). Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. Cancer Letters, 386, 47-56. https://doi.org/10.1016/j.canlet.2016.11.010