Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non‐selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α‐tubulin acetylation with no impact on histone acetylation but failed to show any anti‐cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co‐inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti‐cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off‐target effects.
Lead optimization represents the tedious process of fine-tuning lead compounds from biologically active hits to suitable drug candidates for clinical trials. By chemically modifying a hit structure, an improved compound can be obtained in terms of activity, selectivity, and pharmacokinetic ADME (absorption, distribution, metabolism, and excretion) properties. The carboxylic acid moiety is known to be a crucial functionality in many pharmaceutically active compounds. Despite its common use as a key functionality in drugs, its presence in a lead molecule is often associated with poor pharmacokinetic properties and toxicity. In this literature overview, we discuss how the shortcomings of a carboxylic acid can be circumvented by replacing this functionality with bioisosteres. In this way, the positive aspects of this moiety, such as its activity, for example, by virtue of its capacity to form hydrogen bonds, can be maintained or even improved. To that end, we provide an overview of the most promising carboxylic acid bioisosteres and discuss a selection of synthetic routes towards the main functionalities.
Recent studies point towards the possible disadvantages of using hydroxamic acid-based zinc-binding groups in HDAC inhibitors due to mutagenicity issues. In this work, we elaborated on our previously developed Tubathian series, a class of highly selective thiaheterocyclic HDAC6 inhibitors, by replacing the benzohydroxamic acid function by an alternative zinc chelator,, an aromatic trifluoromethyl ketone. Unfortunately, these compounds showed a reduced potency to inhibit HDAC6 as compared to their hydroxamic acid counterparts. In agreement, the most active trifluoromethyl ketone was unable to influence the growth of SK-OV-3 ovarian cancer cells nor to alter the acetylation status of tubulin and histone H3. These data suggest that replacement of the zinc-binding hydroxamic acid function with a trifluoromethyl ketone zinc-binding moiety within reported benzohydroxamic HDAC6 inhibitors should not be considered as a standard strategy in HDAC inhibitor development.
The synthesis of HDAC6 inhibitors has attracted considerable interest in medicinal chemistry because of their drug potential in different therapeutic areas. In this paper, the preparation of two classes of indoline‐based benzhydroxamic acids is presented, bearing either the classical 4‐hydroxycarbamoylbenzyl or a hitherto unexplored 2‐[4‐(hydroxycarbamoyl)phenoxy]ethyl group, which were shown to exhibit complete HDAC6 inhibition at 10 μM. Furthermore, evaluation of these compounds for interaction with cholinesterases (AChE and BChE) and monoamine oxidases (A and B) revealed some of them to be moderate inhibitors in that respect as well.
Histone deacetylases (HDACs) are enzymes pursued as drug
targets
in various cancers and several non-oncological conditions, such as
inflammation and neurodegenerative disorders. In the past decade,
HDAC inhibitors (HDACi) have emerged as relevant pharmaceuticals,
with many efforts devoted to the development of new representatives.
However, the growing safety concerns regarding the established hydroxamic
acid-based HDAC inhibitors tend to drive current research more toward
the design of inhibitors bearing alternative zinc-binding groups (ZBGs).
This Perspective presents an overview of all non-hydroxamic
acid ZBGs that have been incorporated into the clinically approved
prototypical HDACi, suberoylanilide hydroxamic acid (vorinostat).
This provides the unique opportunity to compare the inhibition potential
and biological effects of different ZBGs in a direct way, as the compounds
selected for this Perspective differ only in their ZBG. To that end,
different strategies used to select a ZBG, its properties, activity,
and liabilities are discussed.
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