Development of the first small molecule histone deacetylase 6 (HDAC6) degraders

  • Bioorg Med Chem Lett. 2018 Aug 1;28(14):2493-2497. doi: 10.1016/j.bmcl.2018.05.057.
Ka Yang  1 ,  Yanling Song  2 ,  Haibo Xie  1 ,  Hao Wu  1 ,  Yi-Ting Wu  3 ,  Eric D Leisten  1 ,  Weiping Tang  4
Affiliations
  • 1. School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA.
  • 2. 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).
  • 3. School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan (current address).
  • 4. School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: [email protected].
PMID: 29871848 DOI: 10.1016/j.bmcl.2018.05.057
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
Cereblon; Degrader; Epigenetic; HDAC; PROTAC; Thalidomide.
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