6cw8

Publication Abstract from PubMed

Dual- or multi-target 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 rational 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.

Discovery of the first-in-class dual histone deacetylase-proteasome inhibitor.,Bhatia S, Krieger V, Groll M, Osko J, Ressing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK J Med Chem. 2018 Oct 26. doi: 10.1021/acs.jmedchem.8b01487. PMID:30365892^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.