Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.
J Med Chem
; 61(22): 10299-10309, 2018 11 21.
Article
em En
| MEDLINE
| ID: mdl-30365892
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Inibidores de Histona Desacetilases
/
Inibidores de Proteassoma
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article