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Discovery of the First-in-Class Dual Histone Deacetylase–Proteasome Inhibitor
Ist Teil von
Journal of medicinal chemistry, 2018-11, Vol.61 (22), p.10299-10309
Ort / Verlag
United States: American Chemical Society
Erscheinungsjahr
2018
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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.