The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
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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“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]
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“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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Cites
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Self-citationPhthalimide conjugation as a strategy for in vivo target protein degradation
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Items 101–134 of 134
Wen, Y., Yang, C., Ye, Y., Shen, Z., & Wang, C. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104920 · Cited by 3
Recent Innovative Advances in the Discovery of Selective HDAC6 Inhibitors
Tavares, M. T., & Shen, S. (2021) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0040 · Cited by 3
PROTACs: Principles and Mechanisms
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Zhang, F., Dong, Y., Yang, Z., Guo, C. J., Zhang, X., Shang, Y., Li, L., Gao, M. Y., & Pang, Y. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114831 · Cited by 2
Application of PROTAC Technology in Drug Development
Kharkar, P. S., & Jadhav, A. L. (2022) · Methods and principles in medicinal chemistry · doi:10.1002/9783527827855.ch10 · Cited by 2
Effective Tubulin Degradation by Rationally Designed Proteolysis Targeting ChimerasPreprint
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Targeted Protein Degradation of Metalloenzymes
O’Herin, C., & Cohen, S. M. (2025) · Wiley eBooks · doi:10.1002/0471266949.bmc303
PROTACS- targeted protein degradation as a path to precision cancer therapeutics
Gatley, H. R., Fisher, P. B., & Das, S. K. (2025) · Advances in cancer research · doi:10.1016/bs.acr.2025.08.001
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Tsymliakov, M., Hanl, M., Enns, J., Zhai, S., Ferretti, E., König, P., Kousa, R., Tu, J., Steinebach, C., Gütschow, M., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c02045 · Cited by 1
Development of Hydrophobic Tag Based HDAC6 Degrader for Ulcerative Colitis Treatment
Lu, D., Liu, R., Zheng, C., Sun, Y., Gao, J., & Luan, Y. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00246
BindingDB (2024) · UC San Diego · doi:10.7270/q26t0rwh
BindingDB Entry 50018757: PROTACs: New method to degrade transcription regulating proteins.
BindingDB (2024) · UC San Diego · doi:10.7270/q2280cvr
BindingDB Entry 50013121: Discovery of a PROTAC targeting ALK with in vivo activity.
BindingDB (2022) · UC San Diego · doi:10.7270/q25h7m0f
BindingDB Entry 50021665: The application of PROTAC in HDAC.
BindingDB (2025) · UC San Diego · doi:10.7270/q2474gjr
BindingDB Entry 50021137: HDAC-targeting epigenetic modulators for cancer immunotherapy.
BindingDB (2025) · UC San Diego · doi:10.7270/q2rx9hnw
BindingDB (2023) · UC San Diego · doi:10.7270/q2vm4h9b
BindingDB Entry 50018797: A bibliometric analysis of PROTAC from 2001 to 2021.
BindingDB (2024) · UC San Diego · doi:10.7270/q28p64s7
BindingDB (2024) · UC San Diego · doi:10.7270/q2x352pq
BindingDB Entry 50016856: Medicinal chemistry updates of novel HDACs inhibitors (2020 to present).
BindingDB (2023) · UC San Diego · doi:10.7270/q2348qfg
BindingDB (2026) · UC San Diego · doi:10.7270/q2ff3z70
BindingDB (2023) · UC San Diego · doi:10.7270/q25t3qmb
BindingDB (2024) · UC San Diego · doi:10.7270/q2vh5t9d
Metadata
- 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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