scholarly journals In Search of Selectivity: Design, Synthesis, and Biological Evaluation of New Classes of HDAC Inhibitors

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 63
Author(s):  
L. M. Viranga Tillekeratne ◽  
Ayad Ayad Al-Hamashi ◽  
Samkeliso Dlamini ◽  
William Taylor ◽  
Radhika Koranne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Metal Binding ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Design And Synthesis ◽  
Epigenetic Modulation

Epigenetic regulation of gene expression without changing DNA sequences is a promising strategy in developing therapeutic agents for human diseases, especially cancer. Histone deacetylases (HDACs) are a family of enzymes involved in epigenetic modulation of gene expression by chromatin remodeling. Deacetylation of the lysine side chains of histones by HDAC proteins renders DNA transcriptionally inactive, resulting in the inhibition of expression of tumor suppressor genes, leading to tumorigenesis and tumor progression. Therefore, inhibiting HDAC enzymes has become an attractive strategy to modulate gene expression as a strategy for developing anticancer drugs. There are currently four FDA-approved cancer drugs in clinical use, and many more are in different stages of clinical trials. However, their clinical utility is limited due to undesirable side effects, mainly attributed to their lack of selectivity and the presence of a hydroxamic acid moiety as the metal-binding group. There are eighteen different isoforms of HDACs belonging to four classes that have been identified in humans. A major challenge in HDAC inhibitor development is how to make them selective for these HDAC isoforms and classes. We report the design and synthesis of new classes of HDAC inhibitors and the evaluation of their anticancer activity and selectivity.

scholarly journals Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Nutrients ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 1120 ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Drug Efficacy ◽  
Histone Deacetylation ◽  
Epigenetic Modifiers

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

Zinc Dependent Histone Deacetylase Inhibitors in Cancer Therapeutics: Recent Update

2020 ◽  
Vol 26 (40) ◽  
pp. 7212-7280 ◽  
Author(s):  
Faria Sultana ◽  
Kesari Lakshmi Manasa ◽  
Siddiq Pasha Shaik ◽  
Srinivasa Reddy Bonam ◽  
Ahmed Kamal
Keyword(s):  
Gene Expression ◽  
Drug Therapy ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Combination Drug Therapy ◽  
Combination Drug

Background: Histone deacetylases (HDAC) are an important class of enzymes that play a pivotal role in epigenetic regulation of gene expression that modifies the terminal of core histones leading to remodelling of chromatin topology and thereby controlling gene expression. HDAC inhibitors (HDACi) counter this action and can result in hyperacetylation of histones, thereby inducing an array of cellular consequences such as activation of apoptotic pathways, generation of reactive oxygen species (ROS), cell cycle arrest and autophagy. Hence, there is a growing interest in the potential clinical use of HDAC inhibitors as a new class of targeted cancer therapeutics. Methodology and Result: Several research articles spanning between 2016 and 2017 were reviewed in this article and presently offer critical insights into the important strategies such as structure-based rational drug design, multi-parameter lead optimization methodologies, relevant SAR studies and biology of various class of HDAC inhibitors, such as hydroxamic acids, benzamides, cyclic peptides, aliphatic acids, summarising the clinical trials and results of various combination drug therapy till date. Conclusion: This review will provide a platform to the synthetic chemists and biologists to cater the needs of both molecular targeted therapy and combination drug therapy to design and synthesize safe and selective HDAC inhibitors in cancer therapeutics.

scholarly journals Histone deacetylases (HDACs): characterization of the classical HDAC family

2003 ◽  
Vol 370 (3) ◽  
pp. 737-749 ◽  
Author(s):  
Annemieke J.M. de RUIJTER ◽  
Albert H. van GENNIP ◽  
Huib N. CARON ◽  
Stephan KEMP ◽  
André B.P. van KUILENBURG
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Building Blocks ◽  
Post Translational Modification ◽  
Comprehensive Overview ◽  
Almost All ◽  
Enzyme Complexes

Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect. Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. The aim of this review is to give a comprehensive overview of the structure, function and tissue distribution of members of the classical histone deacetylase (HDAC) family, in order to gain insight into the regulation of gene expression through HDAC activity. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis. This challenging field has generated many fascinating results which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole.

scholarly journals Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1664 ◽  
Author(s):  
Flávia Alves Verza ◽  
Umashankar Das ◽  
Ana Lúcia Fachin ◽  
Jonathan R. Dimmock ◽  
Mozart Marins
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Histone Deacetylases ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Cancer Therapies ◽  
Cancer Pathways ◽  
Eukaryotic Chromatin ◽  
New Cancer Therapies ◽  
Cycle Regulation

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.

scholarly journals Computational QSAR model combined molecular descriptors and fingerprints to predict HDAC1 inhibitors

2018 ◽  
Vol 34 ◽  
pp. 52-58 ◽  
Author(s):  
Jingsheng Shi ◽  
Guanglei Zhao ◽  
Yibing Wei
Keyword(s):  
Histone Deacetylases ◽  
Computational Models ◽  
Nearest Neighbor ◽  
Dynamic Balance ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Qsar Model ◽  
Support Vector ◽  
C4.5 Decision Tree ◽  
Fold Cross Validation

The dynamic balance between acetylation and deacetylation of histones plays a crucial role in the epigenetic regulation of gene expression. It is equilibrated by two families of enzymes: histone acetyltransferases and histone deacetylases (HDACs). HDACs repress transcription by regulating the conformation of the higher-order chromatin structure. HDAC inhibitors have recently become a class of chemical agents for potential treatment of the abnormal chromatin remodeling process involved in certain cancers. In this study, we constructed a large dataset to predict the activity value of HDAC1 inhibitors. Each compound was represented with seven fingerprints, and computational models were subsequently developed to predict HDAC1 inhibitors via five machine learning methods. These methods include naïve Bayes, κ-nearest neighbor, C4.5 decision tree, random forest, and support vector machine (SVM) algorithms. The best predicting model was CDK fingerprint with SVM, which exhibited an accuracy of 0.89. This model also performed best in five-fold cross-validation. Some representative substructure alerts responsible for HDAC1 inhibitors were identified by using MoSS in KNIME, which could facilitate the identification of HDAC1 inhibitors.

scholarly journals Design, Synthesis and Biological Evaluation of N4-Sulfonamido-Succinamic, Phthalamic, Acrylic and Benzoyl Acetic Acid Derivatives as Potential DPP IV Inhibitors

2013 ◽  
Vol 7 (1) ◽  
pp. 39-48 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Ghassan Abu Sheikha ◽  
Mahmoud Al-Sha'er ◽  
Mutasem Taha
Keyword(s):  
Acetic Acid ◽  
Type Ii Diabetes Mellitus ◽  
Biological Evaluation ◽  
Diabetic Patients ◽  
Type Ii ◽  
Design Synthesis ◽  
Multifunctional Protein ◽  
Design And Synthesis ◽  
Dpp Iv

As incidence rate of type II diabetes mellitus continues to rise, there is a growing need to identify novel therapeutic agents with improved efficacy and reduced side effects. Dipeptidyl peptidase IV (DPP IV) is a multifunctional protein involved in many physiological processes. It deactivates the natural hypoglycemic incretin hormone effect. Inhibition of this enzyme increases endogenous incretin level, incretin activity and should restore glucose homeostasis in type II diabetic patients making it an attractive target for the development of new antidiabetic drugs. One of the interesting reported anti- DPP IV hits is Gemifloxacin which is used as a lead compound for the development of new DPP IV inhibitors. In the current work, design and synthesis of a series of N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives was carried out. The synthesized compounds were evaluated for their in vitro anti-DPP IV activity. Some of them have shown reasonable bioactivity, where the most active one 17 was found to have an IC50 of 33.5 μM.

scholarly journals The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

2018 ◽  
Vol 20 (1) ◽  
pp. 102 ◽  
Author(s):  
Justine Habibian ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Protein Phosphorylation ◽  
Cross Talk ◽  
Electrostatic Interactions ◽  
Regulation Of Gene Expression ◽  
Hdac Inhibitors ◽  
Protein Activity ◽  
Histone Protein ◽  
Signal Transduction Protein ◽  
And Function

Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

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