Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents

2020 ◽  
Vol 27 (15) ◽  
pp. 2449-2493 ◽  
Author(s):  
Loredana Cappellacci ◽  
Diego R. Perinelli ◽  
Filippo Maggi ◽  
Mario Grifantini ◽  
Riccardo Petrelli
Keyword(s):  
Clinical Trials ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Rational Drug Design ◽  
Modeling Tools ◽  
Anti Cancer

Histone Deacetylase (HDAC) inhibitors are a relatively new class of anti-cancer agents that play important roles in epigenetic or non-epigenetic regulation, inducing death, apoptosis, and cell cycle arrest in cancer cells. Recently, their use has been clinically validated in cancer patients resulting in the approval by the FDA of four HDAC inhibitors, vorinostat, romidepsin, belinostat and panobinostat, used for the treatment of cutaneous/peripheral T-cell lymphoma and multiple myeloma. Many more HDAC inhibitors are at different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. Also, clinical trials of several HDAC inhibitors for use as anti-cancer drugs (alone or in combination with other anti-cancer therapeutics) are ongoing. In the intensifying efforts to discover new, hopefully, more therapeutically efficacious HDAC inhibitors, molecular modelingbased rational drug design has played an important role. In this review, we summarize four major structural classes of HDAC inhibitors (hydroxamic acid derivatives, aminobenzamide, cyclic peptide and short-chain fatty acids) that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

scholarly journals Mechanism of Action for HDAC Inhibitors—Insights from Omics Approaches

2019 ◽  
Vol 20 (7) ◽  
pp. 1616 ◽  
Author(s):  
Wenbo Li ◽  
Zheng Sun
Keyword(s):  
Clinical Trials ◽  
Enzymatic Activity ◽  
Histone Deacetylase ◽  
Mechanism Of Action ◽  
Histone Deacetylase Inhibitors ◽  
Catalytic Domain ◽  
Hdac Inhibitors ◽  
Mechanistic Studies ◽  
Low Toxicity ◽  
Strict Specificity

Histone deacetylase inhibitors (HDIs) are a class of prominent epigenetic drugs that are currently being tested in hundreds of clinical trials against a variety of diseases. A few compounds have already been approved for treating lymphoma or myeloma. HDIs bind to the zinc-containing catalytic domain of the histone deacetylase (HDACs) and they repress the deacetylase enzymatic activity. The broad therapeutic effect of HDIs with seemingly low toxicity is somewhat puzzling when considering that most HDIs lack strict specificity toward any individual HDAC and, even if they do, each individual HDAC has diverse functions under different physiology scenarios. Here, we review recent mechanistic studies using omics approaches, including epigenomics, transcriptomics, proteomics, metabolomics, and chemoproteomics, methods. These omics studies provide non-biased insights into the mechanism of action for HDIs.

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.

Histone Deacetylase Inhibitors and Papillary Thyroid Cancer

2020 ◽  
Vol 26 ◽  
Author(s):  
Eleftherios Spartalis ◽  
Konstantinos Kotrotsios ◽  
Dimosthenis Chrysikos ◽  
Michael Spartalis ◽  
Stavroula A. Paschou ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Histone Deacetylase ◽  
Papillary Thyroid Cancer ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Potential Effect ◽  
Papillary Thyroid ◽  
Major Response ◽  
Anti Cancer

Background/Aim: Papillary Thyroid Cancer (PTC) is the most common type of endocrine malignancy. Although PTC has an excellent prognosis, recurrent or metastatic disease could affect patients survival. Recent studies show that Histone Deacetylase Inhibitors (HDACIs) might be promising anticancer agents against PTC. The aim of this review is to evaluate the role of HDACIs as an additional modality in PTC treatment and to depict the latest trends of current research on this field. Materials and Methods: This literature review was performed using the MEDLINE database. The search strategy included terms: “thyroid cancer”, “papillary”, “HDAC”, “histone”, and “deacetylase”. Results: Agents, such as Suberoyl Anilide Hydroxamic Acid, Trichostatin A, Valproic Acid, Sodium butyrate, Panobinostat, Belinostat, Romidepsin, CUDC907 and N-Hydroxy-7-(2-naphthylthio)-Hepanomide have shown promising anti-cancer effects on PTC cell lines but fail to trigger major response in clinical trials. Conclusion: HDACIs have no significant effect as monotherapy against PTC but further research needs to be conducted in order to investigate their potential effect when used as an additional modality.

Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy) methyl)-N-hydroxybenzamides/propenamides as Histone Deacetylase Inhibitors and Antitumor Agents

2019 ◽  
Vol 19 (4) ◽  
pp. 546-556
Author(s):  
Duong T. Anh ◽  
Nguyen T. Thuan ◽  
Pham-The Hai ◽  
Le-Thi-Thu Huong ◽  
Nguyen T.K. Yen ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Agents ◽  
Human Cancer ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Inhibitory Potency

Background: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anticancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). Aims: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and Nhydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. Methods: Two new series of N-hydroxybenzamides and N-hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI-H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. Results: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in terms of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in the sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. Conclusions: The two series of N-hydroxybenzamides and N-hydroxypropenamides designed and synthesized were potential HDAC inhibitors and antitumor agents. Further development of these compounds should be warranted.

scholarly journals Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents

2010 ◽  
Vol 3 (1) ◽  
pp. 5 ◽  
Author(s):  
Jiahuai Tan ◽  
Shundong Cang ◽  
Yuehua Ma ◽  
Richard L Petrillo ◽  
Delong Liu
Keyword(s):  
Clinical Trials ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Anti Cancer

Histone Deacetylase Inhibitors in Cancer Therapy

2009 ◽  
Vol 27 (32) ◽  
pp. 5459-5468 ◽  
Author(s):  
Andrew A. Lane ◽  
Bruce A. Chabner
Keyword(s):  
Clinical Trials ◽  
Combination Therapy ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Heat Shock Protein 90 ◽  
Nonhistone Proteins ◽  
Acetylation Status ◽  
And Function

PurposeEpigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors.MethodsIn this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy.ResultsHDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone proteins. HDAC inhibitors have demonstrated antitumor activity in clinical trials, and one drug of this class, vorinostat, is US Food and Drug Administration approved for the treatment of cutaneous T-cell lymphoma. Other inhibitors in advanced stages of clinical development, including depsipeptide and MGCD0103, differ from vorinostat in structure and isoenzyme specificity, and have shown activity against lymphoma, leukemia, and solid tumors. Promising preclinical activity in combination with cytotoxics, inhibitors of heat shock protein 90, and inhibitors of proteasome function have led to combination therapy trials.ConclusionHDAC inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.

Histone Deacetylase Inhibitors: A Review on Class-I Specific Inhibition

2015 ◽  
Vol 15 (9) ◽  
pp. 731-750 ◽  
Author(s):  
Jagannath Behera ◽  
Venkatesan Jayaprakash ◽  
Barij Nayan Sinha
Keyword(s):  
Clinical Trial ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Class I ◽  
Specific Inhibition ◽  
Comprehensive Review ◽  
The Us ◽  
Us Fda

Histone Deacetylase (HDAC) is an established and validated target for the treatment of cancer. It has been attempted to present a comprehensive review on the inhibitors for Class-I Histone Deacetylase enzyme family, reported during the period from 2002 to 2012. This review has summarized the inhibitors, based on their specificity towards different isoforms within this class. Further various recent United State (US) patents and the HDAC inhibitors, used singly or in combination undergoing clinical trial as anticancer agents have been reviewed. Three such inhibitors SAHA, Romidepsin and Belinostat have already been approved by the US-FDA for the treatment of cancer.

scholarly journals Perfluorinated HDAC inhibitors as selective anticancer agents

2017 ◽  
Vol 15 (43) ◽  
pp. 9186-9190 ◽  
Author(s):  
James W. Walton ◽  
Jasmine M. Cross ◽  
Tina Riedel ◽  
Paul J. Dyson
Keyword(s):  
Ovarian Carcinoma ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Carcinoma Cells ◽  
Kidney Cells ◽  
Human Embryonic Kidney ◽  
Human Embryonic Kidney Cells ◽  
Ovarian Carcinoma Cells

Perfluorinated histone deacetylase inhibitors show more potent cytotoxicity and greater selectivity towards ovarian carcinoma cells over human embryonic kidney cells, compared to the clinically-approved inhibitor, SAHA.

Largazole, a Novel Cyclic Peptide Histone Deacetylase Inhibitor, Demonstrates Anti-MM Effects Alone and Increases the Anti-MM Effects of Bortezomib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4925-4925
Author(s):  
Zhi-Wei Li ◽  
Mengyin Hu ◽  
Crystal Leung ◽  
Jeffrey A Steinberg ◽  
Jing Shen ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
In Vitro Studies ◽  
Normal Peripheral Blood ◽  
Anti Cancer

Abstract Abstract 4925 Multiple myeloma (MM) remains an incurable malignancy. Therefore, there is a need for the development of new agents to improve the survival for these patients. Histone acetylation, which is controlled by the balanced activities between histone acetyltransferase (HAT) and histone deacetylase (HDAC), is a major epigenetic modification that contributes to tumorigenesis. Through inhibition of HDAC activity, HDAC inhibitors (HDACis) increase acetylation levels of histones as well as other tumor suppressor gene products; and, therefore, are potential anti-cancer agents. Based on the structures, currently available HDAC inhibitors can be divided into four groups, including hydroxamates, cyclic peptides, aliphatic acids, and benzamides. Largazole is a novel member of the cyclic peptide family of HDACis some of which have shown anti-cancer effects in preclinical studies and early clinical trials including for patients with MM especially when used in combination with the proteasome inhibitor bortezomib. In this study, we have explored the potential anti-MM activity of largazole alone and in combination with bortezomib in preclinical in vitro studies. As demonstrated using the MTS assay, this HDACi inhibits the growth of cells from the MM cell lines RPMI8226, U266 and MM1S with an IC50 of approximately 0.2 μM in all three cell lines. In addition, largazole also induces apoptotic death of MM cells as determined with Annexin V staining followed by flow cytometric analysis. Largazole was also shown to induce histone acetylation in MM cells as determined with Western blot analysis using an antibody against acetyl-histone H4. Furthermore, the combination of this HDACi and bortezomib demonstrated synergistic anti-MM effects in these cell lines. Importantly, treatment of mice with largazole shows excellent tolerability at doses that produce concentrations in vivo that are higher than those shown to produce anti-MM effects in our in vitro studies. Thus, largazole may be a potential new agent for the treatment of MM alone and in combination with bortezomib. Currently, we are evaluating the cytotoxic effects of largazole on normal peripheral blood and bone marrow mononuclear cells in vitro and in vivo using our severe combined immunodeficiency mouse models of human myeloma alone as well as in combination with several other drugs including bortezomib used in the treatment of MM. Updated results from these ongoing studies will be presented at the meeting. Disclosures Berenson: Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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