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 He & 2 others Ao Zhang, Ze Hong Miao

Research output: Contribution to journalArticle

11 Citations (Scopus)

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

Fingerprint

Recombinational DNA Repair
Poly(ADP-ribose) Polymerases
Clinical Trials
Heterografts
Nude Mice
Poly Adenosine Diphosphate Ribose
Neoplasms
Double-Stranded DNA Breaks
Pharmaceutical Preparations
Inhibition (Psychology)
Pharmacokinetics
olaparib
Apoptosis
Cell Line
DNA
Growth

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. / Yuan, Bo; Ye, Na; Song, Shan Shan; Wang, Yu Ting; Song, Zilan; Chen, Hua Dong; Chen, Chuan Huizi; Huan, Xia Juan; Wang, Ying Qing; Su, Yi; Shen, Yan Yan; Sun, Yi Ming; Yang, Xin Ying; Chen, Yi; Guo, Shi Yan; Gan, Yong; Gao, Zhi Wei; Chen, Xiao Yan; Ding, Jian; He, Jin Xue; Zhang, Ao; Miao, Ze Hong.

In: Cancer Letters, Vol. 386, 01.02.2017, p. 47-56.

Research output: Contribution to journalArticle

Yuan, B, Ye, N, Song, SS, Wang, YT, Song, Z, Chen, HD, Chen, CH, Huan, XJ, Wang, YQ, Su, Y, Shen, YY, Sun, YM, Yang, XY, Chen, Y, Guo, SY, Gan, Y, Gao, ZW, Chen, XY, Ding, J, He, JX, Zhang, A & Miao, ZH 2017, 'Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials', Cancer Letters, vol. 386, pp. 47-56. https://doi.org/10.1016/j.canlet.2016.11.010
Yuan, Bo ; Ye, Na ; Song, Shan Shan ; Wang, Yu Ting ; Song, Zilan ; Chen, Hua Dong ; Chen, Chuan Huizi ; Huan, Xia Juan ; Wang, Ying Qing ; Su, Yi ; Shen, Yan Yan ; Sun, Yi Ming ; Yang, Xin Ying ; Chen, Yi ; Guo, Shi Yan ; Gan, Yong ; Gao, Zhi Wei ; Chen, Xiao Yan ; Ding, Jian ; He, Jin Xue ; Zhang, Ao ; Miao, Ze Hong. / Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. In: Cancer Letters. 2017 ; Vol. 386. pp. 47-56.
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AU - Yuan, Bo

AU - Ye, Na

AU - Song, Shan Shan

AU - Wang, Yu Ting

AU - Song, Zilan

AU - Chen, Hua Dong

AU - Chen, Chuan Huizi

AU - Huan, Xia Juan

AU - Wang, Ying Qing

AU - Su, Yi

AU - Shen, Yan Yan

AU - Sun, Yi Ming

AU - Yang, Xin Ying

AU - Chen, Yi

AU - Guo, Shi Yan

AU - Gan, Yong

AU - Gao, Zhi Wei

AU - Chen, Xiao Yan

AU - Ding, Jian

AU - He, Jin Xue

AU - Zhang, Ao

AU - Miao, Ze Hong

PY - 2017/2/1

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N2 - 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.

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