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Towards Selective Inhibition of Histone Deacetylase Isoforms: What Has Been Achieved, Where We Are and What Will Be Next
Author(s) -
Thaler Florian,
Mercurio Ciro
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300413
Subject(s) - romidepsin , vorinostat , depsipeptide , histone deacetylase , computational biology , isozyme , drug discovery , gene isoform , hydroxamic acid , histone , small molecule , chemistry , biochemistry , biology , pharmacology , enzyme , gene , stereochemistry
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.