2-Trifluoroacetylthiophene oxadiazoles as potent and selective class II human histone deacetylase inhibitors

Muraglia, Ester; Altamura, Sergio; Branca, Danila; Cecchetti, Ottavia; Ferrigno, Federica; Orsale, Maria Vittoria; Palumbi, Maria Cecilia; Rowley, Michael; Scarpelli, Rita; Steinkühler, Christian; Jones, Philip

doi:10.1016/j.bmcl.2008.09.076

Cited by 48 publications

(33 citation statements)

References 18 publications

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“…8) [114]. Compound 54, with a simple phenyl substituent, showed no selectivity among class I and II isoforms.…”

Section: Zinc-binding Groupsmentioning

confidence: 96%

Towards Isozyme-Selective HDAC Inhibitors For Interrogating Disease

Gupta¹,

Reid²,

Iyer³

et al. 2012

CTMC

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Histone deacetylase (HDAC) enzymes have emerged as promising targets for the treatment of a wide range of human diseases, including cancers, inflammatory and metabolic disorders, immunological, cardiovascular, and infectious diseases. At present, such applications are limited by the lack of selective inhibitors available for each of the eighteen HDAC enzymes, with most currently available HDAC inhibitors having broad-spectrum activity against multiple HDAC enzymes. Such broad-spectrum activity maybe useful in treating some diseases like cancers, but can be detrimental due to cytotoxic side effects that accompany prolonged treatment of chronic diseased states. Here we summarize progress towards the design and discovery of HDAC inhibitors that are selective for some of the eleven zinc-containing classical HDAC enzymes, and identify opportunities to use such isozyme-selective inhibitors as chemical probes for interrogating the biological roles of individual HDAC enzymes in diseases.

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“…8) [114]. Compound 54, with a simple phenyl substituent, showed no selectivity among class I and II isoforms.…”

Section: Zinc-binding Groupsmentioning

confidence: 96%

Towards Isozyme-Selective HDAC Inhibitors For Interrogating Disease

Gupta¹,

Reid²,

Iyer³

et al. 2012

CTMC

View full text Add to dashboard Cite

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“…Thus, inhibition of peripheral (muscular) HDAC4 may offer an attractive strategy for the treatment of ALS. [43,72,81] …”

Section: Procognitive Effects Of Hdac Inhibitionmentioning

confidence: 98%

“…For instance, compound 19 has an IC 50 against the class II HDAC4 (wt) of 7 nM with >100-fold selectivity over HDAC6 and >1,000-fold over the class I HDAC1 and 3 [72]. They have demonstrated cell permeability, but their promise as drug-like molecules has been compromised by high metabolic turnover.…”

Section: Fig 7 Examples Of Trifluoromethyl Ketonesmentioning

confidence: 99%

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

Bürli¹,

Thomas²,

Beaumont

2010

Topics in Medicinal Chemistry

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Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

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“…HDACIs containing a trifluoromethylketone (TFMK) moiety have been demonstrated to inhibit preferentially class II isoforms (e.g., molecule 5, Tables 3 and 4) [91][92][93]. So far, these inhibitors have been co-crystallized only with human HDAC4 (PDB code 2VQJ) and bacterial HDAH (PDB code 2GH6).…”

Section: Trifluoromethylketone-containing Hdacismentioning

confidence: 98%