Journal
CHEMMEDCHEM
Volume 7, Issue 10, Pages 1815-1824Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201200300
Keywords
cinnamides; epigenetics; histone deacetylases; isoform-selective inhibitors; molecular modeling
Categories
Funding
- Academia Sinica (Taiwan, Republic of China)
- Taiwan National Science Council [NSC100-2320-B-038-006, NSC99-2320-B-001-MY2]
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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 IC50 values in the range of 550 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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