Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors

Tessier, Pierre; Smil, D.; Wahhab, Amal; Leit, Silvana; Rahil, Jubrail; Li, Zuomei; Déziel, Robert; Besterman, Jeffrey M.

doi:10.1016/j.bmcl.2009.08.010

Cited by 57 publications

(50 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compound 6, a previously reported class IIa HDAC inhibitor (28), inhibited the activity of recombinant human HDAC7 (Fig. 4A) and displayed selectivity for this enzyme over HDAC1 (class I) and HDAC6 (class IIb) (IC 50 for HDAC7, 354 nM; IC 50 for HDAC6, 5000 nM; IC 50 for HDAC1, Ͼ10,000 nM).…”

Section: Identification Of Hdac7 As a Candidate Promoter Of Tlr4mentioning

confidence: 79%

See 1 more Smart Citation

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Shakespear

Hohenhaus

Kelly

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Histone deacetylase (HDAC) inhibitors reduce LPS-induced inflammatory mediator production from macrophages, but the relevant HDAC targets are unknown. Results: A specific isoform of Hdac7 amplifies expression of LPS-inducible genes via a HIF-1␣-dependent mechanism in macrophages. Conclusion:The class IIa HDAC Hdac7 promotes inflammatory responses in macrophages. Significance: Hdac7 may be a viable target for developing new anti-inflammatory drugs.

show abstract

Section: Identification Of Hdac7 As a Candidate Promoter Of Tlr4mentioning

confidence: 79%

“…Inhibitor Synthesis-The class IIa HDAC inhibitor, compound 6, was described previously (28). Compound 6 was synthesized by dissolving diphenylacetic acid (800 mg, 3.73 mmol) in 10 ml of dichloromethane before adding thionyl chloride (280 l, 3.87 mmol) under N 2 .…”

Section: Methodsmentioning

confidence: 99%

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Shakespear

Hohenhaus

Kelly

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…S1A). In contrast, diphenylacetohydroxamic acid (DPAH), which blocks class IIa HDACs (26), and tubastatin A, which selectively inhibits class IIb HDAC6 (27), had no effect on ERK1/2 or JNK phosphorylation in NRVMs (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy

Ferguson

Harrison

Jeong

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

100

104

View full text Add to dashboard Cite

Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac hypertrophy through mechanisms that remain poorly understood. We report that class I HDACs function as signal-dependent repressors of cardiac hypertrophy via inhibition of the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. Inhibition of DUSP5 by class I HDACs requires activity of the ERK kinase, mitogenactivated protein kinase kinase (MEK), revealing a self-reinforcing mechanism for promotion of cardiac ERK signaling. In cardiac myocytes treated with highly selective class I HDAC inhibitors, nuclear ERK1/2 signaling is suppressed in a manner that is absolutely dependent on DUSP5. In contrast, cytosolic ERK1/2 activation is maintained under these same conditions. Ectopic expression of DUSP5 in cardiomyocytes results in potent inhibition of agonist-dependent hypertrophy through a mechanism involving suppression of the gene program for hypertrophic growth. These findings define unique roles for class I HDACs and DUSP5 as integral components of a regulatory signaling circuit that controls cardiac hypertrophy.

show abstract

“…These findings candidate class IIa HDACs as druggable targets for immunological diseases [18,71]. -N-hydroxy-2,2-diphenylacetamide and N-hydroxy-9H-xanthene-9-carboxamide (respectively, compound 6 and 13 in the original manuscript) are two diphenylmethylene hydroxamic acids characterized by Besterman group as class IIa HDACs specific inhibitors active in the lM range [80]. Both molecules exhibit a certain degree of symmetry and the second compound could be considered as the rigidification of the diphenyl moiety of the first (Fig.…”

Section: Class Iia Inhibitorsmentioning

confidence: 99%

“…3). This modification increases the specificity of the molecule towards HDAC7 [80]. -N-lauroyl-(l)-phenylalanine is a class IIa HDACi active in the lM range (Fig.…”

Section: Class Iia Inhibitorsmentioning

confidence: 99%

Selective class IIa HDAC inhibitors: myth or reality

Giorgio

Gagliostro

Brancolini

2014

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

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.

show abstract

Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors

Cited by 57 publications

References 35 publications

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy

Selective class IIa HDAC inhibitors: myth or reality

Contact Info

Product

Resources

About