Cited by 134Protein Degradation and InhibitorsHistone Deacetylase Inhibitors ResearchUbiquitin and proteasome pathways

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Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase

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Yang, Ka, Wu, Hao, Zhang, Zhongrui, Leisten, Eric D., Nie, Xueqing, Liu, Binkai, Wen, Zhi, Zhang, Jing, Cunningham, Michael D., Tang, Weiping·2020·ACS Medicinal Chemistry Letters

DOI 10.1021/acsmedchemlett.0c00046PMC PMC7153272

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Abstract

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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Self-citation
Advancing brain tumor therapy: unveiling the potential of PROTACs for targeted protein degradation
Ibrahim, S., Khan, M. U., Noreen, S., Firdous, S., Khurram, I., Rehman, R., Javed, M. A., & Ali, Q. (2025) · Cytotechnology · doi:10.1007/s10616-025-00716-8 · Cited by 3

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: Yang, Ka
Wu, Hao
Zhang, Zhongrui
Leisten, Eric D.
Nie, Xueqing
Liu, Binkai
Wen, Zhi
Zhang, Jing
Tang, Weiping
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)
DOI: 10.1021/acsmedchemlett.0c00046
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: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
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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Development of Selective Histone Deacetylase 6 (HDAC6) Degraders Recruiting Von Hippel–Lindau (VHL) E3 Ubiquitin Ligase

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