奥拉帕尼
聚ADP核糖聚合酶
化学
PI3K/AKT/mTOR通路
药效团
癌细胞
癌症研究
聚合酶
PARP抑制剂
药理学
细胞凋亡
癌症
生物化学
酶
生物
遗传学
作者
Junwei Wang,Hui Li,Guangchao He,Zhaoxing Chu,Kewen Peng,Yiran Ge,Qihua Zhu,Yungen Xu
标识
DOI:10.1021/acs.jmedchem.9b00622
摘要
Concomitant inhibition of PARP and PI3K pathways has been recognized as a promising strategy for cancer therapy, which may expand the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K inhibitors. Among them, compound 15 stands out as the most promising candidate with potent inhibitory activities against both PARP-1/2 and PI3Kα/δ with pIC50 values greater than 8. Compound 15 displayed superior antiproliferative profiles against both BRCA-deficient and BRCA-proficient cancer cells in cellular assays. The prominent synergistic effects produced by the concomitant inhibition of the two targets were elucidated by comprehensive biochemical and cellular mechanistic studies. In vivo, 15 showed more efficacious antitumor activity than the corresponding drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model with a tumor growth inhibitory rate of 73.4% without causing observable toxic effects. All of the results indicate that 15, a first potent dual PARP/PI3K inhibitor, is a highly effective anticancer compound.
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