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Hierarchical virtual screening of the dual MMP-2/HDAC-6 inhibitors from natural products based on pharmacophore models and molecular docking. Wang Yijun,Yang Limei,Hou Jiaying,Zou Qing,Gao Qi,Yao Wenhui,Yao Qizheng,Zhang Ji Journal of biomolecular structure & dynamics The dual-target inhibitors tend to improve the response rate in treating tumors, comparing with the single-target inhibitors. Matrix metalloproteinase-2 (MMP-2) and histone deacetylase-6 (HDAC-6) are attractive targets for cancer therapy. In this study, the hierarchical virtual screening of dual MMP-2/HDAC-6 inhibitors from natural products is investigated. The pharmacophore model of MMP-2 inhibitors is built based on ligands, but the pharmacophore model of HDAC-6 inhibitors is built based on the experimental crystal structures of multiple receptor-ligand complexes. The reliability of these two pharmacophore models is validated subsequently. The hierarchical virtual screening, combining these two different pharmacophore models of MMP-2 and HDAC-6 inhibitors with molecular docking, is carried out to identify the dual MMP-2/HDAC-6 inhibitors from a database of natural products. The four potential dual MMP-2/HDAC-6 inhibitors of natural products, STOCK1 N-46177, STOCK1 N-52245, STOCK1 N-55477, and STOCK1 N-69706, are found. The studies of binding modes show that the screened four natural products can simultaneously well bind with the MMP-2 and HDAC-6 active sites by different kinds of interactions, to inhibit the MMP-2 and HDAC-6 activities. In addition, the ADMET properties of screened four natural products are assessed. These found dual MMP-2/HDAC-6 inhibitors of natural products could serve as the lead compounds for designing the new dual MMP-2/HDAC-6 inhibitors having higher biological activities by carrying out structural modifications and optimizations in the future studies. 10.1080/07391102.2018.1434833
Histone Deacetylase Inhibitors as a Novel Targeted Therapy Against Non-small Cell Lung Cancer: Where Are We Now and What Should We Expect? Damaskos Christos,Tomos Ioannis,Garmpis Nikolaos,Karakatsani Anna,Dimitroulis Dimitrios,Garmpi Anna,Spartalis Eleftherios,Kampolis Christos F,Tsagkari Eleni,Loukeri Angeliki A,Margonis Georgios-Antonios,Spartalis Michael,Andreatos Nikolaos,Schizas Dimitrios,Kokkineli Stefania,Antoniou Efstathios A,Nonni Afroditi,Tsourouflis Gerasimos,Markatos Konstantinos,Kontzoglou Konstantinos,Kostakis Alkiviadis,Tomos Periklis Anticancer research Non-small cell lung cancer constitutes the most common type of lung cancer, accounting for 85-90% of lung cancer, and is a leading cause of cancer-related death. Despite the progress during the past years, poor prognosis remains a challenge and requires further research and development of novel antitumor treatment. Recently, the role of histone deacetylases in gene expression has emerged showing their regulation of the acetylation of histone proteins and other non-histone protein targets and their role in chromatin organization, while their inhibitors, the histone deacetylase inhibitors, have been proposed to have a potential therapeutic role in diverse malignancies, including non-small cell lung cancer. This review article focuses on the role of histone deacetylase inhibitors in the treatment of non-small cell lung cancer and the major molecular mechanisms underlying their antitumor activity recognized so far. 10.21873/anticanres.12189
Inhibitors of histone deacetylase as antitumor agents: A critical review. Manal Mohammed,Chandrasekar M J N,Gomathi Priya Jeyapal,Nanjan M J Bioorganic chemistry Histone deacetylase (EC 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and non-histone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clinical trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chemistry of the molecules of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer. 10.1016/j.bioorg.2016.05.005
The Development Process: from SAHA to Hydroxamate HDAC Inhibitors with Branched CAP Region and Linear Linker. Yang Feifei,Zhao Na,Hu Yunjie,Jiang Cheng-Shi,Zhang Hua Chemistry & biodiversity Histone deacetylases (HDACs) belong to a group of epigenetic regulatory enzymes that participate in modulating the acetylation level of histone lysine residues as well as non-histone proteins, and they play a key role in the regulation of gene expression. HDACs are potential anticancer drug targets highly expressed in various kinds of cancer cells. So far, five small molecules targeting HDACs have been approved for the therapy of cancer, and over 20 inhibitors of HDACs are under different phases of clinical trials. Among them, hydroxamate-based HDAC inhibitors (HDACis) represent a well-investigated series of chemical entities. The current review covers the recent progress in the discovery process, form SAHA to hydroxamate HDAC inhibitors with branched CAP region and linear linker. At the same time, the pharmacological and structure-activity relationship (SAR) studies of the specific derivatives from SAHA and the HDACis with branched CAP region and linear linker are also introduced. 10.1002/cbdv.201900427
An Overview of HDAC Inhibitors and their Synthetic Routes. Peng Xiaopeng,Liao Guochao,Sun Pinghua,Yu Zhiqiang,Chen Jianjun Current topics in medicinal chemistry Epigenetics play a key role in the origin, development and metastasis of cancer. Epigenetic processes include DNA methylation, histone acetylation, histone methylation, and histone phosphorylation, among which, histone acetylation is the most common one that plays important roles in the regulation of normal cellular processes, and is controlled by histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDACs are involved in the regulation of many key cellular processes, such as DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function, and can lead to oncogene activation. As a result, HDACs are considered to be an excellent target for anti-cancer therapeutics like histone deacetylase inhibitors (HDACi) which have attracted much attention in the last decade. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. The primary purpose of this paper is to summarize recent HDAC inhibitors and the synthetic routes as well as to discuss the direction for the future development of new HDAC inhibitors. 10.2174/1568026619666190227221507
Histone Deacetylase (HDAC) Inhibitors - emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration. Ganai Shabir Ahmad,Ramadoss Mahalakshmi,Mahadevan Vijayalakshmi Current neuropharmacology Epigenetic regulation of neuronal signalling through histone acetylation dictates transcription programs that govern neuronal memory, plasticity and learning paradigms. Histone Acetyl Transferases (HATs) and Histone Deacetylases (HDACs) are antagonistic enzymes that regulate gene expression through acetylation and deacetylation of histone proteins around which DNA is wrapped inside a eukaryotic cell nucleus. The epigenetic control of HDACs and the cellular imbalance between HATs and HDACs dictate disease states and have been implicated in muscular dystrophy, loss of memory, neurodegeneration and autistic disorders. Altering gene expression profiles through inhibition of HDACs is now emerging as a powerful technique in therapy. This review presents evolving applications of HDAC inhibitors as potential drugs in neurological research and therapy. Mechanisms that govern their expression profiles in neuronal signalling, plasticity and learning will be covered. Promising and exciting possibilities of HDAC inhibitors in memory formation, fear conditioning, ischemic stroke and neural regeneration have been detailed. 10.2174/1570159x13666151021111609
Chimeric HDAC inhibitors: Comprehensive review on the HDAC-based strategies developed to combat cancer. Hesham Heba M,Lasheen Deena S,Abouzid Khaled A M Medicinal research reviews Recently, molecular hybridization paradigm became an interesting and smart way to defeat the multifaceted cancer disease by a single molecular entity that acts via several mechanisms just like a magic bullet. Also, HDAC is an important epigenetic target in drug discovery, and the HDAC inhibitors showed successful pattern as cytotoxic agents. Because of their flexible structure activity relationship, it was easy to link them to other anticancer scaffolds. So, many dual action HDAC inhibitors have been developed and most of these hybrids have higher potency than the constituting parents in fighting of the cancer cells. This review describes potential applications of chimeric HDAC inhibitors, which simultaneously modulate not only HDAC but also multiple targets, in treatment of relapsing and drug-resistant cancers. We have nearly collected most of the reported dual action HDAC inhibitors yet to provide a comprehensive guide for the drug discovery process for developing more efficient anticancer agents. 10.1002/med.21505
Research Advances in the Use of Histone Deacetylase Inhibitors for Epigenetic Targeting of Cancer. Bai Yu,Ahmad Daid,Wang Ting,Cui Guihua,Li Wenliang Current topics in medicinal chemistry The causes and progression of cancer are controlled by epigenetic processes. The mechanisms involved in epigenetic regulation of cancer development, gene expression, and signaling pathways have been studied. Histone deacetylases (HDACs) have a major impact on chromatin remodeling and epigenetics, making their inhibitors a very interesting area of cancer research. This review comprehensively summarizes the literature regarding HDAC inhibitors (HDACis) as an anticancer treatment published in the past few years. In addition, we explain the mechanisms of their therapeutic effects on cancer. An analysis of the beneficial characteristics and drawbacks of HDACis also is presented, which will assist preclinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy. Future therapeutic strategies may include a combination of HDACis and chemotherapy or other inhibitors to target multiple oncogenic signaling pathways. 10.2174/1568026619666190125145110
Histone Deacetylase Inhibitors in Tumor Immunotherapy. Zhao Li-Ming,Zhang Jie-Huan Current medicinal chemistry BACKGROUND:With an increasing understanding of the antitumor immune response, considerable progress has been made in the field of tumor immunotherapy in the last decade. Inhibition of histone deacetylases represents a new strategy in tumor therapy and histone deacetylase inhibitors have been recently developed and validated as potential antitumor drugs. In addition to the direct antitumor effects, histone deacetylase inhibitors have been found to have the ability to improve tumor recognition by immune cells that may contribute to their antitumor activity. These immunomodolutory effects are desirable, and their in-depth comprehension will facilitate the design of novel regimens with improved clinical efficacy. OBJECTIVE:Our goal here is to review recent developments in the application of histone deacetylase inhibitors as immune modulators in cancer treatment. METHODS:Systemic compilation of the relevant literature in this field. RESULTS & CONCLUSION:In this review, we summarize recent advances in the understanding of how histone deacetylase inhibitors alter immune process and discuss their effects on various cytokines. We also discuss the challenges to optimize the use of these inhibitors as immune modulators in cancer treatment. Information gained from this review will be valuable to this field and may be helpful for designing tumor immunotherapy trials involving histone deacetylase inhibitors. 10.2174/0929867324666170801102124
Histone Deacetylase Inhibitors as Anticancer Drugs. Eckschlager Tomas,Plch Johana,Stiborova Marie,Hrabeta Jan International journal of molecular sciences Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities. 10.3390/ijms18071414
Recent Progress in Histone Deacetylase Inhibitors as Anticancer Agents. Cappellacci Loredana,Perinelli Diego R,Maggi Filippo,Grifantini Mario,Petrelli Riccardo Current medicinal chemistry 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. 10.2174/0929867325666181016163110