Identification of Novel, Selective, and Stable Inhibitors of Class II Histone Deacetylases. Validation Studies of the Inhibition of the Enzymatic Activity of HDAC4 by Small Molecules as a Novel Approach for Cancer Therapy

Ontoria, Jesus M.; Altamura, Sergio; Marco, Annalise Di; Ferrigno, Federica; Laufer, Ralph; Muraglia, Ester; Palumbi, Maria Cecilia; Rowley, Michael; Scarpelli, Rita; Schultz‐Fademrecht, Carsten; Serafini, Sergio; Steinkühler, Christian; Jones, Philip

doi:10.1021/jm900555u

Cited by 54 publications

(35 citation statements)

References 34 publications

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“…This structurally unique small molecule inhibitor showed preferential inhibition of HDAC8 (IC 50 =90 nM) vs all other HDACs (>18-fold selectivity over HDACs 1, 2, and 6). In 2008, Jones et al [97,98] reported a series of 5-(trifluoroacetyl)thiophene-2-carboxamides as novel, potent, and selective class II HDACi exemplified by compound 9 (HDAC4 IC 50 =320 nM; HDAC6 IC 50 =310 nM). X-ray crystal structures of HDAC4 with compound 9 demonstrate these compounds are active site inhibitors and bind in their hydrated form.…”

Section: Other Zinc-binding Motifsmentioning

confidence: 99%

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

et al. 2013

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Lysine acetylation is an ancient, evolutionarily conserved, reversible post-translational modification. A multitude of diverse cellular functions are regulated by this dynamic modification, including energy and metabolism, protein folding, transcription, and translation. Gene expression can be manipulated through changes in histone acetylation status, and this process is controlled by the function of 2 opposing enzymes: histone acetyl transferases and histone deacetylases (HDACs). The zinc-dependent HDACs are a family of hydrolases that remove acetyl groups from lysines, and their function can be modulated by the action of small molecule ligands. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small molecule chemotypes. Structural biology has aided the development of potent, and in some cases highly isoformselective, inhibitors that have demonstrated utility in a number of neurological disease models. Continued development and characterization of highly optimized small molecule inhibitors of HDAC enzymes will help refine our understanding of their function and, optimistically, lead to novel therapeutic treatment alternatives for a host of neurological disorders.

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Section: Other Zinc-binding Motifsmentioning

confidence: 99%

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

et al. 2013

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“…binding domain is substituted by a trifluoromethyloxadiazolyl group (TFMO) [26] that highly resembles the trifluoromethylketone (TFMK) adopted by Bottomley and colleagues in their biochemical study of the ZBD [31]. The ring structure of the TFMO group increases its stability with respect to the highly unstable TFMK series of compounds [79]. Moreover, this TFMO moiety, differently from hydroxamate, acts as a non-chelating metal binding group, which interacts with the ''catalytic'' Zn 2?…”

Section: Class Iia Inhibitorsmentioning

confidence: 99%

Selective class IIa HDAC inhibitors: myth or reality

Giorgio

Gagliostro

Brancolini

2014

Cell. Mol. Life Sci.

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The prospect of intervening, through the use of a specific molecule, with a cellular alteration responsible for a disease, is a fundamental ambition of biomedical science. Epigenetic-based therapies appear as a remarkable opportunity to impact on several disorders, including cancer. Many efforts have been made to develop small molecules acting as inhibitors of histone deacetylases (HDACs). These enzymes are key targets to reset altered genetic programs and thus to restore normal cellular activities, including drug responsiveness. Several classes of HDAC inhibitors (HDACis) have been generated, characterized and, in certain cases, approved for the use in clinic. A new frontier is the generation of subtype-specific inhibitors, to increase selectivity and to manage general toxicity. Here we will discuss about a set of molecules, which can interfere with the activity of a specific subclass of HDACs: the class IIa.

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“…A similar thiophene 11 with a trifluoromethyl ketone group was inactive on HDAC6 at the highest concentration tested. [20] This indicates that very subtle differences in the interplay of the different structural elements govern HDAC selectivity in somewhat similar molecules, which warrants further exploration. Key interactions for HDAC6 affinity of 1 could be identified already ( Figure 1) and can be used to guide further synthetic optimization.…”

Section: Wwwchemmedchemorgmentioning

confidence: 99%

Carbamate Prodrug Concept for Hydroxamate HDAC Inhibitors

et al. 2011

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Reversible acetylation of histones and other proteins has emerged over the last 10 years as an important mechanism for cell proliferation and has been identified as a valuable target for anticancer drug design. Acetylation is executed and maintained by the histone acetyltransferases and reversed by their counterparts, histone deacetylases (HDACs). The first HDAC inhibitors have already been approved for therapeutic use, and many additional clinical studies are currently under way. [1][2][3][4] Herein, we describe virtual screening efforts that identified several novel HDAC6 inhibitors with cellular isoform selectivity. In particular, a carbamate-protected hydroxamic acid exhibited improved effects with respect to protein hyperacetylation compared with the parent hydroxamate, possibly because of improved cell permeability. The carbamate structure therefore represents a potential prodrug concept for hydroxamic acidcontaining HDAC inhibitors.HDACs are zinc-dependent amidohydrolases, and 11 human subtypes are known.[5] Among the dozens of nonhistone substrates of HDACs, tubulin has attracted a lot of attention because it is a validated target for established anticancer drugs, such as taxanes, the vinca-alkaloids and their derivatives. Tubulin is deacetylated by a single zinc-dependent HDAC subtype, HDAC6, [6,7] and by the NAD + -dependent histone deacetylase Sirt2.[8] HDAC6-specific inhibitors [9] and nonselective HDAC inhibitors [10] synergize in cytotoxicity with the proteasome inhibitor bortezomib (Velcade), which makes HDAC6 an interesting target for inhibitor development. So far, reports of HDAC6-selective inhibitors are limited [7,11,12,13] compared to nonselective or class I-selective inhibitors.[14] Aiming at novel selective HDAC6 inhibitors, we were particularly interested in whether structure-based virtual screening using a HDAC6 homology model could deliver such compounds.We recently reported a homology model for HDAC6 used for docking studies of hydroxamates.[15] The model was generated by exploiting multiple solved crystal structures of related HDACs as templates. Based on a substructure search for hydroxamates and related zinc binding groups, we identified 252 potential compounds by virtually screening the Maybridge compound collection comprising 55 000 molecules. The docking and subsequent visual inspection of the docking poses showed that, among the compounds with the highest docking scores, several hydroxamate and hydrazide derivatives could be identified. Finally, the five top-ranked compounds (1-5) were selected for in vitro testing.In an initial step, compounds 1-5 were assayed using a rat liver HDAC preparation that contains a mixture of subtypes [14,15] with a fluorescence-based assay. [16] Only the hydroxamate 1 and its carbamate derivative 2 were found to show HDAC inhibition below 100 mm. IC 50 values of 4.8 AE 0.5 mm for 1 and 73.4 AE 5.7 mm for 2 were obtained. The identified hydrazides 3-5 were found to be inactive even though the predicted docking poses suggest an interaction between the ...

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Identification of Novel, Selective, and Stable Inhibitors of Class II Histone Deacetylases. Validation Studies of the Inhibition of the Enzymatic Activity of HDAC4 by Small Molecules as a Novel Approach for Cancer Therapy

Cited by 54 publications

References 34 publications

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

Selective class IIa HDAC inhibitors: myth or reality

Carbamate Prodrug Concept for Hydroxamate HDAC Inhibitors

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