期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 62, 期 3, 页码 1138-1166出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01090
关键词
-
资金
- Deutsche Forschungsgemeinschaft [Ju295/13-1, Si868/13-1]
- Centre National de la Recherche Scientifique (CNRS)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Universite de Strasbourg
- US National Institutes of Health [GM49758]
- Chemistry-Biology Interface training grant [T32 GM071339]
- DOE Office of Science, Brookhaven National Laboratory [DE-SC0012704]
The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the YJ It z preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
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