scholarly journals Epigenetic drug discovery: a success story for cofactor interference

2018 ◽  
Vol 373 (1748) ◽  
pp. 20170069 ◽  
Author(s):  
A. Ganesan
Keyword(s):  
Histone Deacetylases ◽  
Chemical Biology ◽  
Flavin Adenine Dinucleotide ◽  
Dna Methyltransferases ◽  
Histone Acetyltransferases ◽  
Success Story ◽  
Acetyl Coenzyme A ◽  
Structural Modifications ◽  
The Past ◽  
Epigenetic Drug

Within the past two decades, seven epigenetic drugs have received regulatory approval and numerous other candidates are currently in clinical trials. Among the epigenetic targets are the writer and eraser enzymes that are, respectively, responsible for the reversible introduction and removal of structural modifications in the nucleosome. This review discusses the progress achieved in the design and development of inhibitors against the key writer and eraser pairs: DNA methyltransferases and Tet demethylases; lysine/arginine methyltransferases and lysine demethylases; and histone acetyltransferases and histone deacetylases. A common theme for the successful inhibition of these enzymes in a potent and selective manner is the targeting of the cofactors present in the active site, namely zinc and iron cations, S -adenosylmethione, nicotinamide adenine dinucleotide, flavin adenine dinucleotide and acetyl Coenzyme A. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.

scholarly journals Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

2020 ◽  
Vol 14 (1) ◽  
pp. 17
Author(s):  
K. Eurídice Juárez-Mercado ◽  
Fernando D. Prieto-Martínez ◽  
Norberto Sánchez-Cruz ◽  
Andrea Peña-Castillo ◽  
Diego Prada-Gracia ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Dna Methyltransferase ◽  
Structural Diversity ◽  
Dna Methyltransferases ◽  
Dna Methyltransferase Inhibitors ◽  
Epigenetic Drug ◽  
Ic50 Values ◽  
Dietary Component ◽  
Approved Drugs ◽  
Epigenetic Processes

Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.

scholarly journals DNA Methyltransferase Inhibitors with Novel Chemical Scaffolds

2020 ◽  
Author(s):  
K. Eurídice Juárez-Mercado ◽  
Fernando D. Prieto-Martínez ◽  
Norberto Sánchez-Cruz ◽  
Andrea Peña-Castillo ◽  
Diego Prada-Gracia ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Dna Methyltransferase ◽  
Dna Methyltransferases ◽  
Liver Cancer Cell ◽  
Dna Methyltransferase Inhibitors ◽  
Epigenetic Drug ◽  
Dietary Component ◽  
Approved Drugs ◽  
Extended Connectivity ◽  
Epigenetic Processes

AbstractInhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed Extended Connectivity Interaction Features approach, had an excellent agreement between the experimental IC50 values and docking scores.

scholarly journals Screening of an Epigenetic Drug Library Identifies 4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-Phenyl-Benzeneacetamide that Reduces Melanin Synthesis by Inhibiting Tyrosinase Activity Independently of Epigenetic Mechanisms

2020 ◽  
Vol 21 (13) ◽  
pp. 4589
Author(s):  
Hyerim Song ◽  
Yun Jeong Hwang ◽  
Jae Won Ha ◽  
Yong Chool Boo
Keyword(s):  
Catalytic Activity ◽  
Histone Deacetylases ◽  
Kojic Acid ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanism ◽  
Melanin Synthesis ◽  
Copper Chelation ◽  
Chelating Activity ◽  
Epigenetic Drug

The aim of this study was to identify novel antimelanogenic drugs from an epigenetic screening library containing various modulators targeting DNA methyltransferases, histone deacetylases, and other related enzymes/proteins. Of 141 drugs tested, K8 (4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-phenyl-benzeneacetamide; HPOB) was found to effectively inhibit the α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16-F10 murine melanoma cells without accompanying cytotoxicity. Additional experiments showed that K8 did not significantly reduce the mRNA and protein level of tyrosinase (TYR) or microphthalmia-associated transcription factor (MITF) in cells, but it potently inhibited the catalytic activity TYR in vitro (IC50, 1.1–1.5 µM) as compared to β-arbutin (IC50, 500–700 µM) or kojic acid (IC50, 63 µM). K8 showed copper chelating activity similar to kojic acid. Therefore, these data suggest that K8 inhibits cellular melanin synthesis not by downregulation of TYR protein expression through an epigenetic mechanism, but by direct inhibition of TYR catalytic activity through copper chelation. Metal chelating activity of K8 is not surprising because it is known to inhibit histone deacetylase (HDAC) 6 through zinc chelation. This study identified K8 as a potent inhibitor of cellular melanin synthesis, which may be useful for the treatment of hyperpigmentation disorders

scholarly journals Antiviral therapy of chronic hepatitis C: 30 years success story

2019 ◽  
Vol 91 (11) ◽  
pp. 110-115
Author(s):  
D T Abdurakhmanov ◽  
T P Rozina ◽  
E N Nikulkina ◽  
E Z Burnevich ◽  
E L Tanashuk ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Therapy ◽  
Chronic Hepatitis C ◽  
Antiviral Action ◽  
Success Story ◽  
Treatment Regimens ◽  
The Past ◽  
C 30

Exactly 30 years ago, hepatitis C virus was identified. Over the years, tremendous success has been achieved in the treatment of hepatitis C, which is currently considered to be an almost completely curable disease. The review presents the main stages in the development of hepatitis C antiviral therapy, the efficacy of various treatment regimens. The greatest progress in treatment was noted over the past 5 years when drugs with direct antiviral action appeared and began to be widely used, including in Russia, which ensure the elimination of the virus in 90-95% of cases.

P.2.e.017 DNA methylation is selectively altered in bipolar disorder and linked to DNA methyltransferases and histone deacetylases mRNAs levels

2012 ◽  
Vol 22 ◽  
pp. S285-S286
Author(s):  
C. D'Addario ◽  
B. Dell'Osso ◽  
A. Di Francesco ◽  
M.C. Palazzo ◽  
B. Benatti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bipolar Disorder ◽  
Histone Deacetylases ◽  
Dna Methyltransferases

scholarly journals The Histone Deacetylases HosA and HdaA Affect the Phenotype and Transcriptomic and Metabolic Profiles of Aspergillus niger

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 520 ◽  
Author(s):  
Xuejie Li ◽  
Lijie Pan ◽  
Bin Wang ◽  
Li Pan
Keyword(s):  
Metabolic Pathways ◽  
Histone Deacetylases ◽  
Chromatin Accessibility ◽  
Growth Stress ◽  
Pigment Production ◽  
Histone Acetyltransferases ◽  
Metabolic Profiles ◽  
Phenotypic Analysis ◽  
Histone Modifying Enzymes ◽  
New Strategies

Histone acetylation is an important modification for the regulation of chromatin accessibility and is controlled by two kinds of histone-modifying enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). In filamentous fungi, there is increasing evidence that HATs and HDACs are critical factors related to mycelial growth, stress response, pathogenicity and production of secondary metabolites (SMs). In this study, seven A. niger histone deacetylase-deficient strains were constructed to investigate their effects on the strain growth phenotype as well as the transcriptomic and metabolic profiles of secondary metabolic pathways. Phenotypic analysis showed that deletion of hosA in A. niger FGSC A1279 leads to a significant reduction in growth, pigment production, sporulation and stress resistance, and deletion of hdaA leads to an increase in pigment production in liquid CD medium. According to the metabolomic analysis, the production of the well-known secondary metabolite fumonisin was reduced in both the hosA and hdaA mutants, and the production of kojic acid was reduced in the hdaA mutant and slightly increased in the hosA mutant. Results suggested that the histone deacetylases HosA and HdaA play a role in development and SM biosynthesis in A. niger FGSC A1279. Histone deacetylases offer new strategies for regulation of SM synthesis.

scholarly journals Histone Deacetylation Inhibitors as Therapy Concept in Sepsis

2019 ◽  
Vol 20 (2) ◽  
pp. 346 ◽  
Author(s):  
Andreas von Knethen ◽  
Bernhard Brüne
Keyword(s):  
Organ Failure ◽  
Expression Profile ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Histone Deacetylation ◽  
Histone Acetyltransferases ◽  
Open Chromatin ◽  
Nucleosome Structure ◽  
Active Transcription ◽  
Anti Inflammatory

Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance.

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