期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 14, 页码 2493-2497出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.05.057
关键词
HDAC; Degrader; PROTAC; Cereblon; Thalidomide; Epigenetic
资金
- University of Wisconsin-Madison
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 hi-jacking 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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