Abstract
The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.
Highlights
Histone deacetylases (HDACs) are part of the epigenetic machinery
The pharmacophore is described as a ‘pseudomolecule’, which is composed of common pharmacophoric interaction fields (PIFs), (Fig. 3B) and common atom-centred pseudopharmacophoric fields (Fig. 3C)
By analysing the ChEMBL collection in details, we realised that simultaneous inhibitory information related to four HDAC isoforms, representing class I (HDAC2, HDAC8) and class II HDACs (HDAC4, histone deacetylase isoform 6 (HDAC6)), is reported only for 93 compounds, here referred to as the HDAC ChEMBL dataset (Table S2)
Summary
Histone deacetylases (HDACs) are part of the epigenetic machinery. Within histone acetyltransferases, they are responsible for controlling the acetylation status of histones, regulating chromatin condensation and gene expression. HDAC6 is a mainly cytosolic isoform that targets non-histone substrates, such as α-tubulin, HSP90, and cortactin controlling microtubule-dependent cell motility and degradation of misfolded proteins through the aggresome pathway These properties make HDAC6 a target of interest because of its potential role in cancer and neurodegenerative disorders[3,4,5,6,7,8]. Considerable efforts have been made to develop HDAC inhibitors, and some of them have even reached the market as antitumor drugs, such as Vorinostat (SAHA), Romidepsin (FK228, a prodrug), Belinostat (PXD-101), and Panabinostat (LBH-589, Farydak, www.fda.gov)[9,10] All of these non-selective HDAC inhibitors share the prototypical pharmacophoric scheme for HDAC inhibition, consisting of a zinc binding group (ZBG), a hydrophobic linker or spacer to fit the catalytic site channel, and a cap group targeting the channel rim (Fig. 1A)[11].
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