化学
聚ADP核糖聚合酶
立体化学
体内
IC50型
喹唑啉
核糖
PARP抑制剂
药理学
体外
生物化学
酶
聚合酶
生物
医学
生物技术
作者
Jie Zhou,Ming Ji,Xiaoyu Wang,Hailong Zhao,Ran Cao,Jing Jin,Yan Li,Xianhong Chen,Sheng Li,Xiaoguang Chen,Bo Xu
标识
DOI:10.1021/acs.jmedchem.1c01522
摘要
Inhibiting PARP-1/2 offered an important arsenal for cancer treatments via interfering with DNA repair of cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24, PARP-1: IC50 = 0.51 nM, PARP-2: IC50 = 23.11 nM; compound 32, PARP-1: IC50 = 1.31 nM, PARP-2: IC50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.
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