奥拉帕尼
PARP1
聚ADP核糖聚合酶
PARP抑制剂
癌症研究
癌细胞
药理学
细胞凋亡
DNA修复
合成致死
DNA损伤
聚合酶
生物
癌症
分子生物学
医学
生物化学
DNA
内科学
作者
Bo Yuan,Na Ye,Shan Song,Yu Ting Wang,Zilan Song,Hua Dong Chen,Chuan Huizi Chen,Xia Juan Huan,Ying Qing Wang,Yi Su,Yangmei Shen,Yi Sun,Xin Yang,Yi Chen,Shi Yan Guo,Yong Gan,Zhi Gao,Xiao Yan Chen,Jian Ding,Jin He,Ao Zhang,Ze Hong Miao
标识
DOI:10.1016/j.canlet.2016.11.010
摘要
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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