Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase
Open accessAbstract
Histone deacetylase 6 (HDAC6) is involved in multiple cellular processes such as aggresome formation, protein stability, and cell motility. Numerous HDAC6-selective inhibitors have been developed as cellular chemical tools to elucidate the function of HDAC6. Since HDAC6 has multiple domains that cannot be studied by HDAC6-selective inhibitors, CRISPR-CAS9 and siRNA/shRNA have been employed to elucidate the nonenzymatic functions of HDAC6. However, these genetic methods have many limitations. Proteolysis targeting chimera (PROTAC) is an emerging technology for the development of small molecules that can quickly remove the entire protein in cells. We previously developed multifunctional HDAC6 degraders that can recruit cereblon (CRBN) E3 ubiquitin ligase. These HDAC6 degraders can degrade not only HDAC6 but also neo-substrates of CRBN. They are excellent candidates for the development of anticancer therapeutics, but the multifunctional nature of the CRBN-based HDAC6 degraders has limited their utility as specific chemical probes for the study of HDAC6-related cellular pathways. Herein we report the development of the first cell-permeable HDAC6-selective degraders employing Von Hippel–Lindau (VHL) E3 ubiquitin ligase, which does not have any known neo-substrates. The DC 50 ’s of the most potent compound 3j are 7.1 nM and 4.3 nM in human MM1S and mouse 4935 cell lines, respectively. The D max ’s of 3j in these two cell lines are 90% and 57%, respectively.
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STAT3 protein degradation can be achieved more efficiently and sustainably than technologies that use STAT3 mRNA.
“First, STAT3 protein degradation can be achieved more efficiently and sustainably than technologies that use STAT3 mRNA with the characteristic of rapid degradation (50, 51).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [50]
The paper’s Abstract describes PROTACs as inducing efficient, rapid protein degradation with potentially sustained downstream effects, and presents them as an alternative to siRNA/shRNA. Its experiments concern HDAC6, however; it does not establish that STAT3 degradation is more efficient or sustainable than STAT3 mRNA-targeting technologies. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCRBN-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 [135]
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“First, STAT3 protein degradation can be achieved more efficiently and sustainably than technologies that use STAT3 mRNA with the characteristic of rapid degradation (50, 51).”
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Light-Controllable PROTACs for Temporospatial Control of Protein Degradation
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Designing HDAC-PROTACs: Lessons Learned So Far
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Histone Deacetylases as Epigenetic Targets for Treating Parkinson’s Disease
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Progress of small molecules for targeted protein degradation: PROTACs and other technologies
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Small-Molecule PROTACs for Cancer Immunotherapy
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Targeting histone deacetylases: Emerging applications beyond cancer
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PROTAC chemical probes for histone deacetylase enzymes
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Monoselective Histone Deacetylase 6 PROTAC Degrader Shows In Vivo Tractability
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Development of a Bestatin-SAHA Hybrid with Dual Inhibitory Activity against APN and HDAC
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Recent advances in epigenetic proteolysis targeting chimeras (Epi-PROTACs)
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Recent Advances in Small Molecular Modulators Targeting Histone Deacetylase 6
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Targeting micro-environmental pathways by PROTACs as a therapeutic strategy
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ZX703: A Small-Molecule Degrader of GPX4 Inducing Ferroptosis in Human Cancer Cells
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PROTACs: Promising Approaches for Epigenetic Strategies to Overcome Drug Resistance
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Self-citationAdvancing brain tumor therapy: unveiling the potential of PROTACs for targeted protein degradation
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- Authors
- Yang, K., Wu, H., Zhang, Z., Leisten, E. D., Nie, X., Liu, B., Wen, Z., Zhang, J., Cunningham, M. D., & Tang, W.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Tang, Weiping
- ORCID
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-03-18
- Volume
- 11
- Issue
- 4
- Pages
- 575-581
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC7153272
- OpenAlex
- W3011548650
- Cited by
- 124
- References
- 47
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 14 · 2023: 23 · 2022: 27 · 2021: 19 · 2020: 10
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (???R01 CA152108???)
- 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, PROTACs, VHL E3 ubiquitin ligase, chemical probes, MM.1S cells, aggresome formation, anticancer agents
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