Title:Targeting Class IIa HDACs: Insights from Phenotypes and Inhibitors
Volume: 28
Issue: 42
Author(s): Ligong Liu*, Lilong Dong, Erika Bourguet and David P. Fairlie*
Affiliation:
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland,
Brisbane, QLD 4072, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular
Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- Australian Research Council
Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of
Queensland, Brisbane, QLD 4072, Australia
- Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- Centre for Inflammation and Disease Research, Institute for Molecular
Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia
- Australian Research Council
Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of
Queensland, Brisbane, QLD 4072, Australia
Keywords:
Drug discovery, epigenetic regulation, phenotype, histone deacetylase, HDAC isoforms, class IIa HDAC, inhibitor, catalytic domain inhibitor.
Abstract: 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.
