期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 4, 页码 1635-1644出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm201438f
关键词
-
资金
- Irish Health Research Board (HRB) [HRB/2007/2]
- Enterprise Ireland [EI- CFTD/06/110]
- Cancer Research Ireland (CRI)
- Irish Higher Education Authority
- European Commission [274988]
Prostate cancer (PCa) therapy typically involves administration of classical antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the figand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and figand-based virtual screening. Compounds demonstrate full (true) antagonism in AR with low micromolar potency, selectivity over estrogen receptors alpha and beta and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据