On the inhibition of histone deacetylase 8 |
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| Authors: | Guillermina Estiu Nathan West Ralph Mazitschek Edward Greenberg James E Bradner Olaf Wiest |
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| Institution: | 1. Walther Cancer Research Center and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670, USA;2. Broad Institute of Harvard University and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA;3. Division of Hematologic Neoplasia, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA;4. Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA |
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| Abstract: | Histone deacetylases are key regulators of gene expression and have recently emerged as important therapeutic targets for cancer and a growing number of non-malignant diseases. Many widely studied inhibitors of HDACs such as SAHA are thought to have low selectivity within or between the human HDAC isoform classes. Using an isoform-selective assay, we have shown that a number of the known inhibitors have in fact a low activity against HDAC8. Based on the wealth of structural information available for human HDAC8, we use a combination of docking and molecular dynamics simulations to determine the structural origin of the experimental results. A close relationship is found between the activity and the high surface malleability of HDAC8. These results provide a rationale for the recently described ‘linkerless’ HDAC8 selective inhibitors and design criteria for HDAC8 selective inhibitors. |
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