: 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 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 were available. Given that the numbers of genes affected by silencing class IIa HDACs are 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 for other HDAC ligands.

Abbreviations: BRAC2, breast cancer type 2 susceptibility protein; GFP, green fluorescent protein; HR, homologous recombination; HTS, high throughput screening.

Malaria, caused by Plasmodium parasites, results in >400,000 deaths annually. There is no effective vaccine, and new drugs with novel modes of action are needed because of increasing parasite resistance to current antimalarials. Histone deacetylases (HDACs) are epigenetic regulatory enzymes that catalyze post-translational protein deacetylation and are promising malaria drug targets. Here, we describe quantitative structure–activity relationship models to predict the antiplasmodial activity of hydroxamate-based HDAC inhibitors. The models incorporate P. falciparum in vitro activity data for 385 compounds containing a hydroxamic acid and were subject to internal and external validation. When used to screen 22 new hydroxamate-based HDAC inhibitors for antiplasmodial activity, model A7 (external accuracy 91%) identified three hits that were subsequently verified as having potent in vitro activity against P. falciparum parasites (IC50 = 6, 71, and 84 nM), with 8 to 51-fold selectivity for P. falciparum versus human cells.

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