Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
Abstract
Histone deacetylase 6 (HDAC6) primarily catalyzes the removal of acetyl group from the side chain of acetylated lysine residues in cytoplasmic proteins such as α-tubulin and HSP90. HDAC6 is involved in multiple disease-relevant pathways. Based on the proteolysis targeting chimera strategy, we previously developed the first HDAC6 degrader by tethering a pan-HDAC inhibitor with cereblon (CRBN) E3 ubiquitin ligase ligand. We herein report our new generation of multifunctional HDAC6 degraders by tethering selective HDAC6 inhibitor Nexturastat A with CRBN ligand that can synergize with HDAC6 degradation for the antiproliferation of multiple myeloma (MM). This new class of degraders exhibited improved potency and selectivity for the degradation of HDAC6. After the optimization of the linker length and linking positions, we discovered potent HDAC6 degraders with nanomolar DC 50 and promising antiproliferation activity in multiple myeloma (MM) cells.
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CRBN-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 [11]
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Self-citation
- Authors
- Wu, H., Yang, K., Zhang, Z., Leisten, E. D., Li, Z., Xie, H., Liu, J., Smith, K. A., Novakova, Z., Barinka, C., & Tang, W.
- Affiliations
- University of Wisconsin–Madison (US)
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic
- Corresponding author
- Tang, Weiping
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-07-04
- Volume
- 62
- Issue
- 15
- Pages
- 7042-7057
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2955112289
- Cited by
- 180
- References
- 68
- Citations by year
- 2026: 11 · 2025: 25 · 2024: 20 · 2023: 23 · 2022: 33 · 2021: 30 · 2020: 33 · 2019: 5
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wisconsin Alumni Research Foundation
- European Regional Development Fund (CZ.1.05/1.1.00/02.0109)
- Grantov? Agentura Cesk? Republiky (15-19640S)
- Akademie Ved Cesk? Republiky (RVO: 86652036)
- University of Wisconsin-Madison
- UW School of Pharmacy
- 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 › Chemical Synthesis and Analysis
- Keywords
- HDAC6, PROTACs, multiple myeloma, linker optimization, protein degradation, antiproliferative activity
- MeSH terms
- Histone Deacetylase 6, Drug Development, Antineoplastic Agents, Dose-Response Relationship, Drug, HeLa Cells, Humans, Multiple Myeloma, Cell Proliferation, Histone Deacetylase Inhibitors, Hep G2 Cells, MCF-7 Cells
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 ›
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