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ID: ALA4118247
Journal: Bioorg Med Chem Lett
Title: Development of the first small molecule histone deacetylase 6 (HDAC6) degraders.
Authors: Yang K, Song Y, Xie H, Wu H, Wu YT, Leisten ED, Tang W.
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.
CiteXplore: 29871848