Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
- MeSH
- buňky Hep G2 MeSH
- HeLa buňky MeSH
- histondeacetylasa 6 antagonisté a inhibitory metabolismus MeSH
- inhibitory histondeacetylas farmakologie terapeutické užití MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- mnohočetný myelom farmakoterapie enzymologie MeSH
- proliferace buněk účinky léků fyziologie MeSH
- protinádorové látky farmakologie terapeutické užití MeSH
- vyvíjení léků metody MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- HDAC6 protein, human MeSH Prohlížeč
- histondeacetylasa 6 MeSH
- inhibitory histondeacetylas MeSH
- protinádorové látky 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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