Reversible histone acetylation is a key post-translational modification that regulates gene expression by modifying chromatin architecture . This process is controlled by two opposing enzyme families. Histone acetyltransferases (HATs) catalyze the addition of an acetyl or acyl group on the ε-amino group of lysine residues of histone proteins . These modifications result in neutralizing the positive charge on lysine residues, reducing the interactions between histone proteins and DNA, and finally leading to gene-transcription activation . The histone deacetylases (HDACs) remove the acetyl or acyl groups from the modified lysine residues, resulting in the formation of condensed chromatin and transcriptional gene silencing . In humans, eighteen different HDACs have been identified and classified according to their sequence homology to yeast into four classes. Class I (HDAC1, 2, 3, and 8), class II (HDAC4, 5, 6, 7, 9, and 10), and class IV (HDAC11), which are zinc-dependent deacetylases, and class III (sirtuins SIRT1-7), which are NAD + dependent deacetylases . Besides acting on modified lysine residues of histones, HDACs have numerous non-histone substrates . Recently, HDACs have gained growing interest as potential therapeutic targets as these enzymes can modify the aberrant epigenetic conditions associated with cancer development . Several HDAC inhibitors (HDACi) have been developed and tested as potential therapies for solid tumors and blood malignancies . Most HDACi share a common pharmacophoric feature consisting of three distinct groups as follows: a zinc binding group (ZBG), a capping group, and a linker . The ZBG is responsible for chelating Zn 2+ ion in the active site of HDACs. Different ZBGs have been used for the development of HDACi, e.g. hydroxamic acids, 2-aminobenzamides, short-chain fatty acids, thiols, alkylhydrazides, and others . In addition, cyclic peptides without a ZBG have been reported as HDACi . To date, four HDACi have been approved by the US Food and Drug Administration (FDA) for the treatment of different types of hematological malignancies. These include the hydroxamate-based inhibitors vorinostat, belinostat, and panobinostat, as well as the thiol-prodrug/depsipeptide (romidepsin) . Although hydroxamic acid is a potent and widely used ZBG, it was observed that hydroxamate-based HDAC inhibitors often lack HDAC-isoform selectivity and show off-target side effects . In addition, they are associated with cellular mutagenicity and genotoxicity . Compared with hydroxamate-based HDACi, the 2-aminobenzamide HDACi exhibit improved class I HDAC selectivity and lower toxicity (Fig. ) . Several clinical studies revealed that hematological toxicities associated with HDACi may limit their therapeutic window, and this is a main reason to exclude several potent candidates from further drug development . Therefore, cell-specific inhibition of such epigenetic targets could be a promising strategy to overcome off-target side effects.