Histone HDAC6 inhibitor

Kozikowski AP et al (2008) Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6. J Med Chem 51(15) 4370-4373... 

Smil DV et al (2009) Novel HDAC6 isoform selective chiral small molecule histone deacetylase inhibitors. Bioorg Med Chem Lett 19(3) 688-692... 

Haggarty, S.J., Koeller, K.M., Wong, J.C., Grozinger, C.M. and Schreiber, S.L. (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proceedings of the National Academy of Sciences of the United States of America, 100, 4389 394. 

Many proteins rely upon post-translational modification for activity, subcellular localisation or to alter their structure and/or stabiltiy and some of these modifications are reversible. Reversible acetylation for esunple requires the combined action of acetylases (aka acetyltransfoiases) and deacetylases which work n ether to maintain the appropriate acetylation level. It was only just over ten years ago when these enzymes were first identified and in the case of the first deacetylase an inhibitor of the enzyme was used as a probe to purify the protein itself Reversible protein acetylation has been the subject of intense investigation ever since. Although re-seardi has focussed on histone (de)acetylation and its consequences, it is important to consider alternative in vivo substrates. Human histone deacetylase 6 (HDAC6) is a mbulin deacetylase for example (see ref. 2). 

In addition to enzyme assays, HDAC inhibitors are usually evaluated in cancer cell lines, where they potently inhibit growth proliferation to provide a cell-based phenotypic readout of activity. The cellular potency of HDAC inhibitors can exceed their activity in enzyme assays, as the precise HDAC isoforms that drive proliferation in a given cell type may be unknown. In any case, growth inhibition data should be supplemented with evidence to confirm that it is due to HDAC inhibition and not off-target effects. Typically, confirmatory evidence involves Western blotting of client proteins such as histones for nuclear HDACs or tubulin for HDAC6 to detect an increase in acetylation levels, or changes in a downstream biomarker such as induction of the cyclin-dependent kinase inhibitor p21. 

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