title: Towards selective inhibition of histone deacetylase isoforms: what has been achieved, where we are and what will be next.
abstract: Histone deacetylases (HDACs) are widely studied targets for the treatment of cancer and other diseases. Up to now, over twenty HDAC inhibitors have entered clinical studies and two of them have already reached the market, namely the hydroxamic acid derivative SAHA (vorinostat, Zolinza) and the cyclic depsipeptide FK228 (romidepsin, Istodax) that have been approved for the treatment of cutaneous T-cell lymphoma (CTCL). A common aspect of the first HDAC inhibitors is the absence of any particular selectivity towards specific isozymes. Some of molecules resulted to be “pan”-HDAC inhibitors, while others are class I selective. In the meantime, the knowledge of HDAC biology has continuously progressed. Key advances in the structural biology of various isozymes, reliable molecular homology models as well as suitable biological assays have provided new tools for drug discovery activities. This Minireview aims at surveying these recent developments as well as the design, synthesis and biological characterization of isoform-selective derivatives.
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000077337:Vorinostat
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007527:Isoenzymes; D000077337:Vorinostat; C087123:romidepsin; D006655:Histone Deacetylases