Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors

https://doi.org/10.1016/j.bmcl.2007.02.064Get rights and content

Abstract

In this report, we describe new HDAC inhibitors designed to exploit a unique sub-pocket in the HDAC8 active site. These compounds were based on inspection of the available HDAC8 crystal structures bound to various inhibitors, which collectively show that the HDAC8 active site is unusually malleable and can accommodate inhibitor structures that are distinct from the canonical ‘zinc binding group-linker-cap group’ structures of SAHA, TSA, and similar HDAC inhibitors. Some inhibitors based on this new scaffold are >100-fold selective for HDAC8 over other class I and class II HDACs with IC50 values <1 μM against HDAC8. Furthermore, treatment of human cells with the inhibitors described here shows a unique pattern of hyperacetylated proteins compared with the broad-spectrum HDAC inhibitor TSA.

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Acknowledgments

We thank Chris Roessler for early work on this project. Figure 2, Figure 3, Figure 6 were generated with PyMol (Delano Scientific). This work was supported by the Research Corporation’s Cottrell College Science Award #CC5955 (S.M.U.) and The Gladstone Institutes (E.V.).

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