Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Hep G2 Cells MeSH
- HeLa Cells MeSH
- Histone Deacetylase 6 antagonists & inhibitors metabolism MeSH
- Histone Deacetylase Inhibitors pharmacology therapeutic use MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Multiple Myeloma drug therapy enzymology MeSH
- Cell Proliferation drug effects physiology MeSH
- Drug Development methods MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- HDAC6 protein, human MeSH Browser
- Histone Deacetylase 6 MeSH
- Histone Deacetylase Inhibitors MeSH
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 DC50 and promising antiproliferation activity in multiple myeloma (MM) cells.
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