Development of the first small molecule histone deacetylase 6 (HDAC6) degraders
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.
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CRBN-based PROTACs recruiting a pan-HDAC inhibitor AB3 or HDAC6 selective binder nexturastat A resulted in specific degradation of HDAC6.
“CRBN-based PROTACs recruiting a pan-HDAC inhibitor AB3 or a HDAC6 selective binder nexturastat A resulted in specific degradation of HDAC6.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [136]
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References 65 · Cited by 190
- Authors
- Yang, K., Song, Y., Xie, H., Wu, H., Wu, Y.-T., Leisten, E. D., & Tang, W.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Tang, Weiping
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 28
- Issue
- 14
- Pages
- 2493-2497
- ISSN
- 0960-894X (ISSN-L)
- OpenAlex
- W2805067921
- Cited by
- 190
- References
- 65
- Citations by year
- 2026: 14 · 2025: 24 · 2024: 14 · 2023: 20 · 2022: 31 · 2021: 25 · 2020: 39 · 2019: 21 · 2018: 2
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- HDAC6, histone deacetylase inhibitors, targeted protein degradation, small-molecule degraders, ubiquitin-proteasome system, bifunctional molecules, selective protein degradation
- MeSH terms
- Histone Deacetylase 6, Dose-Response Relationship, Drug, Humans, Structure-Activity Relationship, Thalidomide, Molecular Structure, Small Molecule Libraries
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