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]
Experimental — accuracy not yet measuredIn the citing paper
“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
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
Role for a bidentate ribonuclease in the initiation step of RNA interference
Bernstein, E., Caudy, A. A., Hammond, S. M., & Hannon, G. J. (2001) · Nature · doi:10.1038/35053110 · Cited by 5,018
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
HDAC6 is a microtubule-associated deacetylase
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.-F., & Yao, T.-P. (2002) · Nature · doi:10.1038/417455a · Cited by 2,403
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., Brownell, J. E., Burke, K. E., Cardin, D. P., Critchley, S., et al. (2009) · Nature · doi:10.1038/nature07884 · Cited by 1,990
Self-citationPhthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
Falkenberg, K. J., & Johnstone, R. W. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4360 · Cited by 1,564
Histone-deacetylase inhibitors: novel drugs for the treatment of cancer
Johnstone, R. W. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd772 · Cited by 1,515
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Cited by
Sorted by citations
Proteolysis-targeting chimeras (PROTACs) in cancer therapy
Li, X., Pu, W., Zheng, Q., Ai, M., Chen, S., & Peng, Y. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01434-3 · Cited by 389
Targeted protein degradation: advances in drug discovery and clinical practice
Zhong, G., Chang, X., Xie, W., & Zhou, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02004-x · Cited by 326
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
He, M., Cao, C., Ni, Z., Liu, Y., Song, P., Hao, S., He, Y., Sun, X., & Rao, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00999-9 · Cited by 283
Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras
Bemis, T. A., Clair, J. J. L., & Burkart, M. D. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00482 · Cited by 250
Targeting histone deacetylases for cancer therapy: Trends and challenges
Liang, T., Wang, F., Elhassan, R. M., Cheng, Y., Tang, X., Chen, W., Fang, H., & Hou, X. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.02.007 · Cited by 222
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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