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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141
PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852
Ubiquitin and ubiquitin-like proteins as multifunctional signals
Welchman, R., Gordon, C., & Mayer, R. J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1700 · Cited by 849
The world of protein acetylation
Drazic, A., Myklebust, L. M., Ree, R., & Arnesen, T. (2016) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2016.06.007 · Cited by 847
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 830
Three proteins define a class of human histone deacetylases related to yeast Hda1p
Grozinger, C. M., Hassig, C. A., & Schreiber, S. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.9.4868 · Cited by 770
Bali, P., Pranpat, M., Bradner, J., Balasis, M., Fiskus, W., Guo, F., Rocha, K., Kumaraswamy, S., Boyapalle, S., Atadja, P., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500186200 · Cited by 755
HDAC6 Modulates Cell Motility by Altering the Acetylation Level of Cortactin
Zhang, X. M., Yuan, Z., Zhang, Y., Yong, S., Salas-Burgos, A., Koomen, J. M., Olashaw, N., Parsons, J. T., Yang, X., Dent, S., et al. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.033 · Cited by 731
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.009 · Cited by 686
Modular PROTAC design for the degradation of oncogenic BCR-ABL
Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507634 · Cited by 618
Buckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja209924v · Cited by 569
Mice Lacking Histone Deacetylase 6 Have Hyperacetylated Tubulin but Are Viable and Develop Normally
Zhang, Y., Kwon, S., Yamaguchi, T., Cubizolles, F., Rousseaux, S., Kneissel, M., Cao, C., Li, N., Cheng, H.-L., Chua, K., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01154-06 · Cited by 559
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537
Histone deacetylase 6 structure and molecular basis of catalysis and inhibition
Hai, Y., & Christianson, D. W. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2134 · Cited by 521
A Comprehensive Mathematical Model for Three-Body Binding Equilibria
Douglass, E. F., Miller, C. J., Sparer, G., Shapiro, H., & Spiegel, D. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja311795d · Cited by 472
Galdeano, C., Gadd, M. S., Soares, P., Scaffidi, S., Molle, I. V., Birced, I., Hewitt, S. H., Dias, D. M. G., & Ciulli, A. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5011258 · Cited by 424
HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination
Boyault, C., Sadoul, K., Pabion, M., & Khochbin, S. (2007) · Oncogene · doi:10.1038/sj.onc.1210614 · Cited by 397
The demographics of the ubiquitin system
Clague, M. J., Heride, C., & Urbé, S. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.03.002 · Cited by 389
Zhang, L., Riley-Gillis, B., Vijay, P., & Shen, Y. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-1129 · Cited by 365
An, S., & Fu, L. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.005 · Cited by 363
HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
Simões-Pires, C., Zwick, V., Nurisso, A., Schenker, E., Carrupt, P.-A., & Cuendet, M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-7 · Cited by 341
Expanding the diversity of chemical protein modification allows post-translational mimicry
van Kasteren, S. I., Kramer, H., Jensen, H. H., Campbell, S. J., Kirkpatrick, J. M., Oldham, N. J., Anthony, D. C., & Davis, B. G. (2007) · Nature · doi:10.1038/nature05757 · Cited by 316
Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01572 · Cited by 286
Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy
Ottis, P., & Crews, C. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b01068 · Cited by 228
Chan, K.-H., Zengerle, M., Testa, A., & Ciulli, A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01912 · Cited by 223
Development of the first small molecule histone deacetylase 6 (HDAC6) degraders
Yang, K., Song, Y., Xie, H., Wu, H., Wu, Y.-T., Leisten, E. D., & Tang, W. (2018) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.05.057 · Cited by 190
Self-citationDevelopment of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
Wu, H., Yang, K., Zhang, Z., Leisten, E. D., Li, Z., Xie, H., Liu, J., Smith, K. A., Novakova, Z., Barinka, C., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00516 · Cited by 180
Self-citationEssential role of HDAC6 in the regulation of PD‐L1 in melanoma
Lienlaf, M., Perez-Villarroel, P., Knox, T. J., Pabon, M. M., Sahakian, E., Powers, J. J., Woan, K. V., Lee, C., Cheng, F., Deng, S., et al. (2016) · Molecular Oncology · doi:10.1016/j.molonc.2015.12.012 · Cited by 171
Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs
Girardini, M., Maniaci, C., Hughes, S. J., Testa, A., & Ciulli, A. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.02.048 · Cited by 163
Ottis, P., Palladino, C., Thienger, P., Britschgi, A., Heichinger, C., Berrera, M., Julien-Laferrière, A., Roudnicky, F., Kam‐Thong, T., Bischoff, J. R., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00525 · Cited by 154
Recent advances in the discovery of potent and selective HDAC6 inhibitors
Wang, X.-X., Wan, R.-Z., & Liu, Z.-P. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.10.040 · Cited by 152
HDAC6 Deacetylates and Ubiquitinates MSH2 to Maintain Proper Levels of MutSα
Zhang, M., Xiang, S., Joo, H.-Y., Wang, L., Williams, K. A., Liu, W., Hu, C., Tong, D., Haakenson, J., Wang, C., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.028 · Cited by 151
Plasticity in designing PROTACs for selective and potent degradation of HDAC6
Yang, H., Lv, W., He, M., Deng, H., Li, H., Wu, W., & Rao, Y. (2019) · Chemical Communications · doi:10.1039/c9cc08509b · Cited by 108
de Freitas, R. F., Harding, R., Franzoni, I., Ravichandran, M., Mann, M. K., Ouyang, H., Lautens, M., Santhakumar, V., Arrowsmith, C. H., & Schapira, M. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00258 · Cited by 67
Targeted inhibition of histone deacetylase 6 in inflammatory diseases
Ran, J., & Zhou, J. (2019) · Thoracic Cancer · doi:10.1111/1759-7714.12974 · Cited by 63
Role of the HDAC6/STAT3 pathway in regulating PD-L1 expression in osteosarcoma cell lines
Keremu, A., Aimaiti, A., Liang, Z., & Zou, X. (2018) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-018-3721-6 · Cited by 53
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
