Discovery of the First-in-Class Dual Histone Deacetylase–Proteasome Inhibitor

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.