Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
| Autor: | Haibo Xie, Ziyuan Li, Eric D Leisten, Cyril Barinka, Jin Liu, Zhongrui Zhang, Ka Yang, Kerry A. Smith, Hao Wu, Weiping Tang, Zora Novakova |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Antineoplastic Agents
Histone Deacetylase 6 01 natural sciences 03 medical and health sciences Drug Development Drug Discovery Humans 030304 developmental biology Cell Proliferation 0303 health sciences biology Dose-Response Relationship Drug Chemistry Cereblon Proteolysis targeting chimera Hep G2 Cells HDAC6 Ligand (biochemistry) Hsp90 0104 chemical sciences Ubiquitin ligase Histone Deacetylase Inhibitors 010404 medicinal & biomolecular chemistry Biochemistry Acetylation biology.protein MCF-7 Cells Molecular Medicine Multiple Myeloma Linker HeLa Cells |
| Zdroj: | Journal of medicinal chemistry. 62(15) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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