Abstract:
:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent 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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Reßing N,Sönnichsen M,Osko JD,Schöler A,Schliehe-Diecks J,Skerhut A,Borkhardt A,Hauer J,Kassack MU,Christianson DW,Bhatia S,Hansen FKdoi
10.1021/acs.jmedchem.9b01888subject
Has Abstractpub_date
2020-09-24 00:00:00pages
10339-10351issue
18eissn
0022-2623issn
1520-4804journal_volume
63pub_type
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