Abstract |
Histone deacetylases (HDACs) are a family of enzymes that play a crucial role in biological process and diseases. In contrast to other isozymes, HDAC8 is uniquely incapable of histone acetylation. In order to delineate its physiological function, we developed HDAC8-selective inhibitors using knowledge-based design combined with structural modeling techniques. Enzyme inhibitory analysis demonstrated that some of the resulting compounds (22 b, 22 d, 22 f, and 22 g) exhibited anti-HDAC8 activity superior to PCI34051, a known HDAC8-specific inhibitor, with IC(50) values in the range of 5-50 nM. Among them, compound 22 d showed antiproliferative effects toward several human lung cancer cell lines (A549, H1299, and CL1-5); it exhibited cytotoxicity against human lung CL1-5 cells similar to that of SAHA yet without significant cytotoxicity for normal IMR-90 cells. Expression profiling of HDAC isoforms in three cancer cell lines indicated that the HDAC8 level in CL1-5 is higher than that in H1299 and CL1-1 cells, a result consistent with the differential cytotoxicity of compound 22 d. These results suggest the effectiveness of our design concept, which may lead to a tool compound for studying the specific role of HDAC8 in cellular biological processes.
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Authors | Wei-Jan Huang, Yi-Ching Wang, Shi-Wei Chao, Chen-Yui Yang, Liang-Chieh Chen, Mei-Hsiang Lin, Wen-Chi Hou, Mei-Yu Chen, Tai-Lin Lee, Ping Yang, Chung-I Chang |
Journal | ChemMedChem
(ChemMedChem)
Vol. 7
Issue 10
Pg. 1815-24
(Oct 2012)
ISSN: 1860-7187 [Electronic] Germany |
PMID | 22907916
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Chemical References |
- Amides
- Cinnamates
- Histone Deacetylase Inhibitors
- Repressor Proteins
- HDAC8 protein, human
- Histone Deacetylases
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Topics |
- Amides
(chemical synthesis, chemistry, toxicity)
- Binding Sites
- Cell Line, Tumor
- Cell Survival
(drug effects)
- Cinnamates
(chemical synthesis, chemistry, toxicity)
- Drug Design
- Half-Life
- HeLa Cells
- Histone Deacetylase Inhibitors
(chemical synthesis, chemistry, toxicity)
- Histone Deacetylases
(metabolism)
- Humans
- Molecular Docking Simulation
- Repressor Proteins
(antagonists & inhibitors, metabolism)
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