Ligong Liu*, Lilong Dong, Erika Bourguet and David P. Fairlie* Pages 8628 - 8672 ( 45 )
This review summarizes key literature defining the phenotypes of individual class IIa HDAC proteins and compounds that selectively target their enzymatic catalytic domain (CD). The focus is on the effects of class IIa HDACs in physiological and pathological conditions, both in vitro and in vivo, and on their mode of action in regulating genes, upstream proteins and signaling pathways. Phenotype studies further demonstrate either beneficial or detrimental effects of silencing selected class IIa HDACs or their enzymatic properties. We also summarize the knowledge gained from structure-activity relationships of CD inhibitors as well as molecular mechanisms underpinning isozyme selectivity where crystal structures or modelling studies are available. Given that the number of genes affected by silencing class IIa HDACs is much smaller than class I, the role of gene regulation of class IIa HDACs could be much more selective. Since class IIa HDACs have restricted tissue distributions and multiple functions independent of their CD, targeting the CD of class IIa HDACs could lead to more selective therapeutic agents with significantly fewer side-effects than other HDAC ligands.
Drug discovery, epigenetic regulation, phenotype, histone deacetylase, HDAC isoforms, class IIa HDAC, inhibitor, catalytic domain inhibitor.
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Institut de Chimie Moléculaire de Reims, UMR 7312-CNRS, UFR de Pharmacie de Reims, Université de Reims-Champagne-Ardenne, 51096, Reims Cedex, Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072