Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 22, Pages 10299-10309Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01487
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Funding
- U.S. Department of Energy (DOE) Office of Science User Facility [DE-SC0012704]
- NIH [GM49758]
- Deutsche Forschungsgemeinschaft [SFB1035]
- Fonds der Chemischen Industrie (FCI)
- German Children's Cancer Foundation [110997, 70112951]
- German Carreras Foundation [DJCLS 02R/2016]
- Kinderkrebsstiftung [2016/17]
- Elterninitiative Kinderkrebsldinik eV Dusseldorf
- Research Commission of the Medical Faculty of Heinrich Heine University Dusseldorf [2018-04]
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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.
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