title: The use of diversity profiling to characterize chemical modulators of the histone deacetylases.
abstract: Target specificity and off-target liabilities are routinely monitored during the early phases of drug discovery for most kinase projects. Typically these criteria are evaluated using a profiling panel comprised of a diverse collection of in vitro kinase assays and relates compound structure to potency and selectivity. The success of these efforts has led to the design of similar panels for phosphatase, protease, and epigenetic targets. Here the implementation of an epigenetic profiling panel, comprised of eleven histone deacetylases (HDACs) and one histone acetyltransferase (HAT), was used to evaluate chemical modulators of these enzymes. HDAC inhibitors (HDACi) such as sodium butyrate and trichostatin A demonstrate diverse biological effects which have led to broad speculation about their therapeutic potential in multiple disease states. Some HDACi have demonstrated tumor suppression in vivo and recently Zolinza was the first HDACi approved by the FDA for the treatment of cutaneous T-cell lymphoma. While HDACi have demonstrated therapeutic utility, many of the first generation compounds are pan-inhibitors. Thus, use of an HDAC profiling panel will be essential in achieving isoform specificity of the next generation of inhibitors. To this end, twenty-one compounds, twelve of which are known to have activities against the HDACs, were tested to evaluate the utility of the epigenetic panel. Additionally, these compounds were tested against a larger 72 member enzyme panel comprised of kinase, phosphatase and protease activities. This effort represents the first time these compounds have been profiled with such a broad range of biochemical activities.
authors.affiliation: Amphora Discovery Corp., Research Triangle Park, Durham, NC 27713, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Blackwell
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Norris
authors.forename: Carla M
authors.initials: CM
authors.lastname: Suto
authors.forename: William P
authors.initials: WP
authors.lastname: Janzen
mesh_terms: D016000:Cluster Analysis; D005419:Flavonoids / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D046210:Microfluidic Analytical Techniques; D010447:Peptide Hydrolases / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D059808:Polyphenols; D011480:Protease Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D005419:Flavonoids; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D010636:Phenols; D059808:Polyphenols; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases; D010447:Peptide Hydrolases; D006655:Histone Deacetylases