奥拉帕尼
PARP抑制剂
三阴性乳腺癌
PI3K/AKT/mTOR通路
化学
癌症研究
乳腺癌
聚ADP核糖聚合酶
癌症
药理学
医学
细胞凋亡
内科学
生物化学
酶
聚合酶
作者
Junwei Wang,Guangchao He,Hui Li,Yiran Ge,Shuping Wang,Yungen Xu,Qihua Zhu
标识
DOI:10.1016/j.ejmech.2020.113054
摘要
Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468 cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50 mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.
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