Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 18, Pages 10339-10351Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01888
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Funding
- Forschungskommission [2018-04]
- DSO-Netzwerkverbund, HHU Dusseldorf
- TransOnc priority program of the German Cancer Aid [70112951]
- Deutsches Konsortium fur Translationale Krebsforschung (DKTK) [MYC L*10]
- ERC [Stg 852222]
- Deutsche Forschungsgemeinschaft (DFG) [HA 7783/1-1]
- US National Institutes of Health [GM49758]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [270650915]
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Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multi-component synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.
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