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.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Drug Discovery
- Pharmacology, Toxicology and Pharmaceutics(all)
- Organic Chemistry