scholarly journals A miniaturized readout strategy for endogenous histone deacetylase activity

2015 ◽  
Vol 11 (7) ◽  
pp. 1820-1823 ◽  
Author(s):  
Jan Oliver Jost ◽  
Alfred Hanswillemenke ◽  
Dirk Schwarzer
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Important Drug

Histone deacetylases are important drug targets, which are difficult to characterize due to their poor accessibility.

scholarly journals Histone Deacetylase (HDAC) Inhibitors for the Treatment of Schistosomiasis

2022 ◽  
Vol 15 (1) ◽  
pp. 80
Author(s):  
Ehab Ghazy ◽  
Mohamed Abdelsalam ◽  
Dina Robaa ◽  
Raymond J. Pierce ◽  
Wolfgang Sippl
Keyword(s):  
Life Cycle ◽  
Histone Deacetylase ◽  
Control Strategy ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Hdac Inhibitors ◽  
Parasitic Disease ◽  
Mass Treatment ◽  
Epigenetic Mechanisms ◽  
Histone Deacetylase 8

Schistosomiasis is a major neglected parasitic disease that affects more than 240 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. Schistosomes display morphologically distinct stages during their life cycle and the transformations between stages are controlled by epigenetic mechanisms. The targeting of epigenetic actors might therefore represent the parasites’ Achilles’ heel. Specifically, histone deacetylases have been recently characterized as drug targets for the treatment of schistosomiasis. This review focuses on the recent development of inhibitors for schistosome histone deacetylases. In particular, advances in the development of inhibitors of Schistosoma mansoni histone deacetylase 8 have indicated that targeting this enzyme is a promising approach for the treatment of this infection.

scholarly journals Next-generation of selective histone deacetylase inhibitors

RSC Advances ◽  
2019 ◽  
Vol 9 (34) ◽  
pp. 19571-19583 ◽  
Author(s):  
Feifei Yang ◽  
Na Zhao ◽  
Di Ge ◽  
Yihua Chen
Keyword(s):  
Cancer Treatment ◽  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Histone Deacetylase Inhibitors ◽  
Next Generation ◽  
Epigenetic Drug

Histone deacetylases (HDACs) are clinically validated epigenetic drug targets for cancer treatment.

Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ

2019 ◽  
Author(s):  
Lina Humbeck ◽  
Jette Pretzel ◽  
Saskia Spitzer ◽  
Oliver Koch
Keyword(s):  
Cancer Therapy ◽  
Drug Targets ◽  
Synergistic Effects ◽  
Complex Structure ◽  
Peroxisome Proliferator ◽  
Resistance Development ◽  
Peroxisome Proliferator Activated Receptor ◽  
Starting Point ◽  
Fundamental Research ◽  
Important Drug

Knowledge about interrelationships between different proteins is crucial in fundamental research for the elucidation of protein networks and pathways. Furthermore, it is especially critical in chemical biology to identify further key regulators of a disease and to take advantage of polypharmacology effects. A comprehensive scaffold-based analysis uncovered an unexpected relationship between bromodomain-containing protein 4 (BRD4) and peroxisome-proliferator activated receptor gamma (PPARγ). They are both important drug targets for cancer therapy and many more important diseases. Both proteins share binding site similarities near a common hydrophobic subpocket which should allow the design of a polypharmacology-based ligand targeting both proteins. Such a dual-BRD4-PPARγ-modulator could show synergistic effects with a higher efficacy or delayed resistance development in, for example, cancer therapy. Thereon, a complex structure of sulfasalazine was obtained that involves two bromodomains and could be a potential starting point for the design of a bivalent BRD4 inhibitor.

scholarly journals Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

2021 ◽  
Author(s):  
Chun Yang ◽  
Stéphane Croteau ◽  
Pierre Hardy
Keyword(s):  
Histone Deacetylase ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Muscle Development ◽  
Target Genes ◽  
Human Cancer ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Pathogenesis

Abstract Background HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. Conclusions This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

scholarly journals Histone Deacetylase Enzymes as Potential Drug Targets in Cancer and Parasitic Diseases

2006 ◽  
Vol 2006 ◽  
pp. 1-10 ◽  
Author(s):  
Mehdi Ouaissi ◽  
Ali Ouaissi
Keyword(s):  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Drug Targets ◽  
Large Family ◽  
Current Data ◽  
Functional Study ◽  
Parasitic Diseases ◽  
Antitumor Effects ◽  
Protozoan Infections

The elucidation of the mechanisms of transcriptional activation and repression in eukaryotic cells has shed light on the important role of acetylation-deacetylation of histones mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. Another group belonging to the large family of sirtuins (silent information regulators (SIRs)) has an (nicotinamide adenine dinucleotide)NAD+-dependent HDAC activity. Several inhibitors of HDACs (HDIs) have been shown to exert antitumor effects. Interestingly, some of the HDIs exerted a broad spectrum of antiprotozoal activity. The purpose of this review is to analyze some of the current data related to the deacetylase enzymes as a possible target for drug development in cancer and parasitic diseases with special reference to protozoan infections. Given the structural differences among members of this family of enzymes, development of specific inhibitors will not only allow selective therapeutic intervention, but may also provide a powerful tool for functional study of these enzymes.

A Homogeneous Nonisotopic Histone Deacetylase Activity Assay

2003 ◽  
Vol 8 (1) ◽  
pp. 89-95 ◽  
Author(s):  
Birgit Heltweg ◽  
Manfred Jung
Keyword(s):  
Drug Discovery ◽  
Fluorescence Quenching ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Activity Assay ◽  
Animal Testing ◽  
Hdac Activity

Histone deacetylases (HDACs) are important regulators of transcription, and their inhibitors are a promising class of anticancer agents. The methods for the determination of HDAC activity and its inhibition that are currently available suffer from various drawbacks, such as animal testing, radioactive substrates, or limited throughput. Therefore, a fast nonisotopic method for the measurement of HDAC activity is highly desirable. The authors present such an assay that relies on the fluorescent HDAC substrate developed previously in their group. After incubation of the substrate with the enzyme, a derivatization leads to efficient fluorescence quenching in the deacetylated metabolite. Thus, only the fluorescence emitted by the remaining substrate is detected, which allows for a convenient detection of HDAC activity in a homogeneous format that can be performed on multiwell plate readers. This procedure, called HDASH (histone deacetylase assay—homogeneous), should be a valuable tool in transcriptional research and especially drug discovery. ( Journal of Biomolecular Screening 2003:89-95)

scholarly journals Neuroprotection by Histone Deacetylase-Related Protein

2006 ◽  
Vol 26 (9) ◽  
pp. 3550-3564 ◽  
Author(s):  
Brad E. Morrison ◽  
Nazanin Majdzadeh ◽  
Xiaoguang Zhang ◽  
Aaron Lyles ◽  
Rhonda Bassel-Duby ◽  
...  
Keyword(s):  
Cell Death ◽  
Histone Deacetylase ◽  
Neuronal Death ◽  
Histone Deacetylases ◽  
Essential Feature ◽  
Gene Promoter ◽  
Related Protein ◽  
Phosphatidylinositol 3 Kinase ◽  
Histone Deacetylase 1 ◽  
H3 Acetylation

ABSTRACT The expression of histone deacetylase-related protein (HDRP) is reduced in neurons undergoing apoptosis. Forced reduction of HDRP expression in healthy neurons by treatment with antisense oligonucleotides also induces cell death. Likewise, neurons cultured from mice lacking HDRP are more vulnerable to cell death. Adenovirally mediated expression of HDRP prevents neuronal death, showing that HDRP is a neuroprotective protein. Neuroprotection by forced expression of HDRP is not accompanied by activation of the phosphatidylinositol 3-kinase-Akt or Raf-MEK-ERK signaling pathway, and treatment with pharmacological inhibitors of these pathways fails to inhibit the neuroprotection by HDRP. Stimulation of c-Jun phosphorylation and expression, an essential feature of neuronal death, is prevented by HDRP. We found that HDRP associates with c-Jun N-terminal kinase (JNK) and inhibits its activity, thus explaining the inhibition of c-Jun phosphorylation by HDRP. HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter. Although HDRP lacks intrinsic deacetylase activity, treatment with pharmacological inhibitors of histone deacetylases induces apoptosis even in the presence of ectopically expressed HDRP, underscoring the importance of c-Jun promoter deacetylation by HDRP-HDAC1 in HDRP-mediated neuroprotection. Our results suggest that neuroprotection by HDRP is mediated by the inhibition of c-Jun through its interaction with JNK and HDAC1.

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