Design of novel histone deacetylase inhibitors

Siliphaivanh, Phieng; Harrington, Paul E.; Witter, David J.; Otte, Karin; Tempest, Paul; Kattar, Solomon D.; Kral, Astrid M.; Fleming, James E.; Deshmukh, Sujal V.; Harsch, Andreas; Secrist, Paul; Miller, Thomas A.

doi:10.1016/j.bmcl.2007.05.080

Cited by 43 publications

(28 citation statements)

References 23 publications

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“…S5). Previous studies have established that benzamide-type HDAC inhibitors are selective for class I HDAC enzymes and in particular MS-275 and other o-aminobenzamides show a ϳ4 to 10-fold preference for HDAC1 over HDAC3 (12,25,34 (Fig. 1B), showing that SAHA rapidly reaches equilibrium with these enzymes.…”

Section: Resultsmentioning

confidence: 74%

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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Section: Resultsmentioning

confidence: 74%

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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“…[17] On the other hand, our own work revealed that certain small molecule HDACIs bearing a mecaptoacetamide group as the Zinc Binding Group (ZBG) preferably inhibit HDAC6 over other HDACs. [18] Certain other types of HDACIs containing thiol [19] or benzamide-based ZBGs [20] have also been reported to show some level of isoform selectivity or class selectivity. However, strict head-to-head comparisons of the potency and selectivity of the non-hydroxamate based HDACIs over those containing a hydroxamate group as the ZBGs are relatively rare.…”

Section: Introductionmentioning

confidence: 99%

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

et al. 2008

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The histone deacetylases (HDACs) are able to regulate gene expression and inhibitors of the HDACs (HDACIs) hold promise in the treatment of cancer as well as a variety of neurodegenerative diseases. To investigate the possibility to achieve some measure of isoform selectivity in the inhibition of the HDACs, we prepared a small series of 2,4′-diaminobiphenyl ligands functionalized at the para-amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho-amino group. A smaller series of substituted phenylthiazoles was also explored. Some of these newly synthesized ligands show low nM potency in the HDAC inhibition assays and display micromolar to low nanomolar IC 50 values when tested against five pancreatic cancer cell lines. The isoform selectivity of these ligands for the Class I HDACs (HDAC1-3 and 8) and Class IIb HDACs (HDAC6 and HDAC10) together with QSAR studies of their correlation with the lipophilicity are presented. Of particular interest is the HDAC6 selectivity of the mercaptoacetamides.

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“…The large hydrophobic depsipeptide cap group of FK 228 may contribute to its more class I selective properties by interacting with less conserved regions located further away than those reachable by the smaller benzamide cap group of SAHA in the rim of the active site [47]. Interestingly, tubacin and related compounds with structural similarities to SAHA, but with a large cap group, are more selective for HDAC6 than HDAC1, underscoring the importance of the nature of the cap group in discriminating the HDAC isoforms [48, 49]. The interest in the recently isolated marine natural product largazole as a potent HDAC inhibitor stems from many common structural features that it shares with FK 228.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups

Bhansali

Hanigan

Perera

et al. 2014

European Journal of Medicinal Chemistry

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Several largazole analogues with modified surface recognition cap groups were synthesized and their HDAC inhibitory activities were determined. The C7-epimer 12 caused negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal effect on growth. Although previous studies have shown some degree of tolerance of structural changes at C7 position of largazole, these data show the negative effect of conformational change accompanying change of configuration at this position. Similarly, analogue 16a with D-1-naphthylmethyl side chain at C2 too had negligible inhibition of HDAC activity, failed to induce global histone 3 (H3) acetylation in the HCT116 colorectal cancer cell line and demonstrated minimal effect on growth. In contrast, the L-allyl analogue 16b and the L-1-naphthylmethyl analogue 16c were potent HDAC inhibitors, showing robust induction of global H3 acetylation and significant effect on cell growth. The data suggest that even bulky substituents are tolerated at this position, provided the stereochemistry at C2 is retained. With bulky substituents, inversion of configuration at C2 results in loss of inhibitory activity. The activity profiles of 16b and 16c on Class I HDAC1 vs Class II HDAC6 are similar to those of largazole and, taken together with x-ray crystallography information of HDAC8-largazole complex, may suggest that the C2 position of largazole is not a suitable target for structural optimization to achieve isoform selectivity. The results of these studies may guide the synthesis of more potent and selective HDAC inhibitors.

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Design of novel histone deacetylase inhibitors

Cited by 43 publications

References 23 publications

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

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

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

Synthesis and biological evaluation of largazole analogues with modified surface recognition cap groups

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