HDAC6型
乙酰化
化学
组蛋白
组蛋白脱乙酰基酶
泛素连接酶
小分子
蛋白酶体
泛素
生物化学
好斗的
HDAC11型
双功能
组蛋白脱乙酰基酶2
组蛋白乙酰转移酶
HDAC10型
细胞生物学
生物
DNA
基因
催化作用
作者
Kuo‐Ho Yang,Yanling Song,Haibo Xie,Hao Wu,Yi-Ting Wu,Eric D Leisten,Weiping Tang
标识
DOI:10.1016/j.bmcl.2018.05.057
摘要
Histone deacetylases (HDACs) decrease the acetylation level of histones and other non-histone proteins. Over expression of HDACs have been observed in cancers and other diseases. Targeted protein degradation by "hijacking" the natural ubiquitin-proteasome-system (UPS) recently emerged as a novel technology to "knock-out" endogenous disease-causing proteins. We applied this strategy to the development of the first small molecule degraders for zinc-dependent HDACs by conjugating non-selective HDAC inhibitors with E3 ubiquitin ligase ligands. Through cell-based assays, we discovered novel bifunctional molecules (dHDAC6) that could selectively degrade HDAC6. Further mechanistic studies indicated that HDAC6 was selectively removed by the UPS.
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