br General aspects of HDACs br General aspects

General aspects of HDACs
General aspects of HDAC inhibitors Based on the previous elements, inhibitors designed for HDAC have in common a well-admitted pharmacophore model (Fig. 7A). This model is composed of a zinc binding group (ZBG), attached to a linker chain mimicking the lysine side chain and fitting the tubular access to the zinc atom. This chain is terminated by a functional “cap” group, mainly aromatic, interacting with the external surface. A connecting unit between the cap and the linker chain can also be modulated to improve interactions. The commonly described ZBGs are carboxylic acids, very weak binders, thiols, benzamides, and hydroxamic acids, the later leading usually the strongest inhibitors. Unselective first generation inhibitors were proposed based on these elements but it appeared rapidly that the eleven HDAC isoforms could have specific activities [34] requiring selective compounds. For instance selective HDAC4 inhibitors could be useful in Huntington’ disease [54] and the impact of selective HDAC6 inhibitors was described [55]. In our review, we present selected inhibitors and their selectivity when available and those described in PDB files from the Pubmed structure website. As for many other compounds, classical limits have been encountered with HDAC inhibitors: selective delivery in vivo and resistance [56]. The most potent hydroxamic no sodium salt sale ZBG is not very stable in vivo and is rapidly metabolized. SAHA for instance has a short half-live (<2 h) and is glucuronylated. Considering that the epigenetic-driven renormalization of cancer cells needs hours to be achieved, this requires continuous injection of compounds that can generate side effects. These problems can be solved by designing prodrugs or delivery strategies for epigenetic drugs [57]. Alternatively, latest works in the field of HDAC inhibitors indicate that a third generation of inhibitors will emerge, more compliant with pharmacological requirements, in particular regarding the stability of the ZBG. However, HDAC inhibitors often target multiple HDACs and the biological consequences are often unpredictable and underappreciated given the pleiotropic HDAC activities [24], [34]. Pan-HDAC inhibitors may cause numerous side effects. Therefore, selective inhibitors are necessary for each HDAC isoform, and several are tested in preclinal and phase I or II trials for cancer and neurological diseases [24], [34]. Selective inhibitors open a new field to fight parasite diseases [58]. For example, schistosomiasis (bilharzia) is one of the major human neglected parasitic diseases due to worms from the genus Schistosoma with Schistosoma mansoni the most distributed species. Worldwide more than 265 million individuals are infected and 280,000 deaths are reported annually. No effective vaccine is available and the only treatment is praziquantel. However reduced efficiency and resistance to praziquantel are noticed and new therapeutic strategies are necessary. Interestingly Schistosoma mansoni HDAC8 (smHDAC8) which is the most abundant HDAC from class I in this parasite, presents a different architecture in its active pocket from its human HDAC8 homolog (Fig. 5). By structure-based chemical screening, several compounds were identified with specific inhibitory effects on smHDAC8 over the major human HDACs (1 and 6) and able to cause mortality of schistosomes [59], [60]. Thus, targeting epigenetic HDACs could be a valid strategy to fight parasite diseases.
Mechanistic studies
Design of inhibitors
Carboxylic acids Some weak carboxylic acids HDAC inhibitors active in the range of mM concentrations are well known in clinic justifying their use. Abdel-Atty et al. [91] have proposed compounds where the carboxylic acid replaces the usual hydroxamic acid or the amine group in benzamides. The screening against several cancer cells lines gave two compounds with low inhibition while intriguingly, compound 45 (Fig. 13) gave enhanced activity for HDAC2 over HDAC11 (HDAC1 not tested). Molecular modelling with HDLP identified for compound 45 an additional binding mode due to the ketone group in the alkyl chain. From the series a 3D QSAR pharmacophore model was established to define the hydrogen bond acceptor (HBA, green), ring aromatic (RA, orange) and hydrophobic pocket (HYP) required for efficient inhibition.