Isoform-selective histone deacetylase inhibitors

Abstract

Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical trials as anti-cancer drugs. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. This tutorial review focuses on the recent progress toward the identification of class-selective and isoform-selective HDAC inhibitors. The emerging trends suggest that subtle differences in the active sites of the HDAC isoforms can be exploited to dictate selectivity.

Fig. 1

The acetylation state of lysine amino acids are governed by the equilibrium activities of acetyltransferase enzymes and deacetylase enzymes. In the context of gene expression, the lysine residues of histone proteins are key substrates for acetylation.

Fig. 2

Pan-inhibitors TSA and SAHA.

Fig. 3

HDAC inhibitors with a cyclic peptide or cyclic peptide mimic capping group.

Fig. 4

HDAC inhibitors displaying benzamide metal binding moieties.