Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor
| Autor: | Finn K. Hansen, Jeremy D. Osko, Julia Hauer, Arndt Borkhardt, Sanil Bhatia, Viktoria Krieger, David W. Christianson, Heinz Ahlert, Michael Groll, Thomas Kurz, Nina Reßing |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Proteasome Endopeptidase Complex Protein Conformation Apoptosis Histone Deacetylase 6 Article 03 medical and health sciences Ubiquitin Cell Line Tumor Drug Discovery medicine Humans Cytotoxicity Cell Proliferation biology Chemistry HDAC6 Ligand (biochemistry) Histone Deacetylase Inhibitors 030104 developmental biology Aggresome Proteasome Drug Design Proteasome inhibitor Cancer research biology.protein Molecular Medicine Histone deacetylase Proteasome Inhibitors medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 61(22) |
| ISSN: | 1520-4804 |
| Popis: | Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC–proteasome inhibitors for the treatment of hematological malignancies. |
| Databáze: | OpenAIRE |
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