Poly(ADP-ribose)polymerase (PARP) inhibition and anticancer activity of simmiparib, a new inhibitor undergoing clinical trials. (1st February 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Cancer letters. Volume 386(2017)
• Page Start: 47
• Page End: 56
• Publication Date: 2017-02-01
• Subjects: Homologous recombination repair defects -- Olaparib -- Growth inhibition -- Patient-derived xenografts -- Pharmacokinetics; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.11.010
• Languages: English
• ISSNs: 0304-3835

Abstract

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. Highlights: Simmiparib potently inhibits PARP 1/2 and traps PARP 1-DNA complexes. Simmiparib induces DSB accumulation and G2/M arrest in HR-deficient cells. Simmiparib selectively induces apoptosis in HR-deficient cells. Simmiparib exhibits remarkable anticancer activities both in vitro and in vivo. Simmiparib sensitizes HR-proficient cancer cells to anticancer drugs.