|
|||||
|
|
Development of the first small molecule histone deacetylase 6 (HDAC6) degraders |
|
| Authors: | Ka Yang Yanling Song Haibo Xie Hao Wu Yi-Ting Wu Eric D Leisten Weiping Tang |
| Institution: | 1. School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA;2. Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Liaoning 110042, China (current address);3. Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan (current address);4. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA |
| Abstract: | 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. |
| Keywords: | HDAC Degrader PROTAC Cereblon Thalidomide Epigenetic |
| 本文献已被 ScienceDirect 等数据库收录！ | |