摘要
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 (22b, 22d, 22f, and 22g) exhibited anti-HDAC8 activity superior to PCI34051, a known HDAC8-specific inhibitor, with IC50 values in the range of 5-50nM. Among them, compound 22d 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 22d. 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.
原文 | 英語 |
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頁(從 - 到) | 1815-1824 |
頁數 | 10 |
期刊 | ChemMedChem |
卷 | 7 |
發行號 | 10 |
DOIs | |
出版狀態 | 已發佈 - 10月 2012 |
ASJC Scopus subject areas
- 藥物發現
- 一般藥理學、毒理學和製藥學
- 分子醫學
- 生物化學
- 藥理
- 有機化學