2-Trifluoroacetylthiophenes, a novel series of potent and selective class II histone deacetylase inhibitors

Jones, Philip; Bottomley, M.J.; Carfı́, Andrea; Cecchetti, Ottavia; Ferrigno, Federica; Surdo, Paola Lo; Ontoria, Jesus M.; Rowley, Michael; Scarpelli, Rita; Schultz‐Fademrecht, Carsten; Steinkühler, Christian

doi:10.1016/j.bmcl.2008.02.026

Cited by 64 publications

(56 citation statements)

References 10 publications

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“…Hydroxamate-based inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroamic acid (SAHA; Fig. 1A) are believed to be pan-HDAC inhibitors (14 -16); however, recent studies have shown that TSA and SAHA are actually class I-specific inhibitors, and previous results reporting inhibition of class II HDACs were due to class I HDAC contamination (17)(18)(19). Studies of benzamide-based HDAC inhibitors have shown that these compounds are class I-specific inhibitors, and have claimed distinct pharmacological properties of the benzamide HDAC inhibitors due to specific inhibition of class I HDACs (mainly HDAC1 and HDAC3) (20,21).…”

mentioning

confidence: 99%

Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone Deacetylases

Chou

Herman

Gottesfeld

2008

Journal of Biological Chemistry

197

261

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Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cellbased and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC 50 values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K i of ϳ14 nM, 15 times lower than the K i for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators.The link between post-translational modifications by reversible histone acetylation and deacetylation and mRNA transcription has been shown to be one of the key mechanisms of epigenetic gene regulation (1). Acetylation of histone lysine residues, controlled by the histone acetyltransferases and histone deacetylases (HDACs), 2 has been a subject of intense recent research (2-5). Generally, histone hypoacetylation causes transcriptional silencing, whereas histone hyperacetylation results in transcriptional activation of various genes (6 -8). Eighteen HDACs have been identified in the human genome, including the zinc-dependent HDACs (class I, class II, and class IV), and the NAD ϩ -dependent enzymes (class III or sirtuins) (9, 10). HDACs 1, 2, 3, and 8 belong to class I, showing homology to the yeast enzyme RPD3. Class II is further divided into class IIa (HDACs 4, 5, 7, and 9) and IIb (HDAC 6 and 10), according to their sequence homology and domain organization. HDAC11 is the lone member of class IV (9, 11). The sirtuins (class III) are related to the yeast Sir2 protein and are involved in regulation of metabolism and aging (10).To date, a number of small molecule inhibitors of the zincdependent HDACs have been identified (12). These compounds can be broadly grouped in four chemical classes: the hydroxamates, the benzamides, butyrate analogs, and cyclic peptides, such as depsipeptide and related compounds (12, 13). Hydroxamate-based inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroamic acid (SAHA; Fig. 1A) are believed to be pan-HDAC inhibitors (14 -16); however, recent studies have shown that TSA and SAHA...

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mentioning

confidence: 99%

Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone Deacetylases

Chou

Herman

Gottesfeld

2008

Journal of Biological Chemistry

197

261

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“…68,108,109) These selective inhibitors are intriguing both chemically and biologically, and are of interest as candidate therapeutic agents having few side effects. To date, X-ray crystal structures of human HDAC4, 110) HDAC7, 111) HDAC8, [73][74][75] SIRT2 112) and SIRT5 113) have been published. These crystal structures should pave the way for the discovery of novel isoform-selective inhibitors, which will be useful not only as tools for the detailed elucidation of the biological functions of the isoforms, but also in the development of therapeutic agents with few side effects.…”

Section: Resultsmentioning

confidence: 99%

Explorative Study on Isoform-Selective Histone Deacetylase Inhibitors

Suzuki

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members (HDAC1-11 and SIRT1-7) have been identified, but the functions of the HDAC isoforms are not yet fully understood. In addition, some of the HDAC isoforms have been suggested to be associated with various disease states, including cancer and neurodegenerative disorders. Therefore, isoform-selective HDAC inhibitors are of great interest, not only as tools for probing the biological functions of the isoforms, but also as candidate therapeutic agents with few side effects. It was against this background that we initiated research programs to identify isoform-selective HDAC inhibitors. We designed HDAC inhibitors based on the three-dimensional structure of the enzyme and on the proposed catalytic mechanism of HDACs, and found several isoform-selective HDAC inhibitors. Furthermore, we elucidated the functions of HDAC6 by chemical genetic approaches using these inhibitors. The results of this research also suggested the feasibility of using isoform-selective HDAC inhibitors as therapeutic agents.

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“…Interestingly, the structure of a catalytically inactive HDAC 8 mutant bound to an Ac-lysine substrate reveals that an essential conserved aspartic acid located at the mouth of the binding cavity makes two hydrogen bonds to the substrate [10b]. Very recently, small molecule HDACis bound to the catalytic domain of HDAC 4 have also been described [12].…”

Section: Mechanism and X-ray Crystal Structurementioning

confidence: 99%

“…Subsequently, a group at IRBM developed a related series of thiophene trifluoromethyl ketones and showed these to be selective class II HDACis [12].…”

Section: Electrophilic Ketonesmentioning

confidence: 99%