Cited by 180Protein Degradation and InhibitorsHistone Deacetylase Inhibitors ResearchChemical Synthesis and Analysis

Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity

Wu, Hao, Yang, Ka, Zhang, Zhongrui, Leisten, Eric D., Li, Ziyuan, Xie, Haibo, Liu, Jin, Smith, Kerry A. +3 more·2019·Journal of Medicinal Chemistry

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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Crossref · 10.1021/acs.jmedchem.9b00516

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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
Venue
Journal of Medicinal Chemistry
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
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

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