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Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Sep 24; Vol. 63 (18), pp. 10339-10351. Date of Electronic Publication: 2020 Sep 01. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents metabolism
Antineoplastic Agents pharmacology
Bortezomib pharmacology
Cell Line, Tumor
Daunorubicin pharmacology
Drug Screening Assays, Antitumor
Drug Synergism
Epirubicin pharmacology
Histone Deacetylase 6 metabolism
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors metabolism
Humans
Microsomes, Liver metabolism
Molecular Structure
Protein Binding
Structure-Activity Relationship
Tetrazoles chemical synthesis
Tetrazoles metabolism
Histone Deacetylase 6 antagonists & inhibitors
Histone Deacetylase Inhibitors pharmacology
Tetrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32803970
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b01888