LNCaP公司
化学
前列腺癌
雄激素受体
蛋白酶体
癌症研究
细胞生长
细胞培养
蛋白质水解
癌症
癌细胞
药理学
生物化学
内科学
生物
酶
医学
遗传学
作者
Hang Xie,Jing Liang,Yalei Wang,Tianxing Hu,Jinyi Wang,Rui Yang,Jun-Ke Yan,Qiurong Zhang,Xia Xu,Hong‐Min Liu,Ke Yu
标识
DOI:10.1016/j.ejmech.2020.112512
摘要
Targeted protein degradation using small molecules is a novel strategy for drug development. In order to solve the problem of drug resistance in the treatment of prostate cancer, proteolysis-targeting chimeras (PROTAC) was introduced into the design of anti-prostate cancer derivatives. In this work, we synthesized two series of selective androgen receptor degraders (SARDs) containing the hydrophobic degrons with different linker, and then investigated the structure-activity relationships of these hybrid compounds. Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Among them, compound A9 displayed potent inhibitory activity against LNCaP prostate cancer cell line with IC50 values of 1.75 μM, as well as excellent AR degradation activity. Primary mechanism studies elucidated compound A9 arrested cell cycle at G0/G1 phase and induced a mild apoptotic response in LNCaP cells. Further study indicated that the degradation of AR was mediated through proteasome-mediated process. For all these reasons, compound A9 held promising potential as anti-proliferative agent for the development of highly efficient SARDs for drug-resistance prostate cancer therapies.
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