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.

Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320–Mediated Suppression of the Androgen Receptor

“…Of interest, OBP-801 significantly upregulated miR-320a in all three prostate cancer cell lines, while the other HDAC inhibitors, TSA and SAHA, had minimal impact on miR-320a expression. One of the reasons for the difference in reactivation of miR320a by the HDAC inhibitors might be due to the differences of diverse inhibitory activity of each chemical against HDACs (41,42). OBP-801 is a cyclic peptide-based HDAC inhibitor derived from a natural product containing a disulfide bond.…”

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

“…Pan-HDACis have been developed that target more than one class of HDACs and the development of HDACis with isozyme specificity are on the scope [186] . However, HDACis will not specifically target only HIV, instead these drugs induce general chromatin relaxation on cellular genes and so have effects that are no HIV-specific.…”

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

“…Importantly, the HDACi suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) displays such a profile (11). SAHA is an FDA-approved drug for the treatment of subcutaneous T cell lymphoma (12,13), suggesting that administration of SAHA could be a suitable strategy to test the effect of HDACi in AD patients.…”