Yang Ka, Song Yanling, Xie Haibo, Wu Hao, Wu Yi-Ting, Leisten Eric D, Tang Weiping
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Liaoning 110042, China (current address).
Bioorg Med Chem Lett. 2018 Aug 1;28(14):2493-2497. doi: 10.1016/j.bmcl.2018.05.057. Epub 2018 May 30.
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.
组蛋白去乙酰化酶（HDACs）会降低组蛋白和其他非组蛋白的乙酰化水平。在癌症和其他疾病中已观察到HDACs的过表达。最近，通过“劫持”天然泛素-蛋白酶体系统（UPS）进行靶向蛋白质降解作为一种“敲除”内源性致病蛋白的新技术出现。我们通过将非选择性HDAC抑制剂与E3泛素连接酶配体偶联，将该策略应用于开发首个针对锌依赖性HDACs的小分子降解剂。通过基于细胞的检测，我们发现了可选择性降解HDAC6的新型双功能分子（dHDAC6）。进一步的机制研究表明，HDAC6被UPS选择性清除。
