scholarly journals Development of hydroxamate-based histone deacetylase inhibitors of bis-substituted aromatic amides with antitumor activities

MedChemComm ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 1828-1837 ◽  
Author(s):  
Di Ge ◽  
Lina Han ◽  
Feifei Yang ◽  
Na Zhao ◽  
Yang Yang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Antitumor Activities ◽  
Aromatic Amide

Previously, we designed and synthesized a series of bis-substituted aromatic amide-based histone deacetylase (HDAC) inhibitors.

A hybrid of thiazolidinone with the hydroxamate scaffold for developing novel histone deacetylase inhibitors with antitumor activities

2016 ◽  
Vol 14 (5) ◽  
pp. 1727-1735 ◽  
Author(s):  
Feifei Yang ◽  
Shihong Peng ◽  
Yunqi Li ◽  
Liqiang Su ◽  
Yangrui Peng ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Antitumor Activities

A series of novel histone deacetylase (HDAC) inhibitors were designed, synthesized and evaluated based on the strategies of a hybrid of the classic pharmacophore of HDAC inhibitors with the thiazolidinone scaffold.

scholarly journals The Effect of Vicinal Difluorination on the Conformation and Potency of Histone Deacetylase Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3974
Author(s):  
A. Daryl Ariawan ◽  
Flora Mansour ◽  
Nicole Richardson ◽  
Mohan Bhadbhade ◽  
Junming Ho ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Molecular Conformations ◽  
Fluorinated Analogs ◽  
Selective Agents ◽  
Isoform Selectivity

Histone deacetylase enzymes (HDACs) are potential targets for the treatment of cancer and other diseases, but it is challenging to design isoform-selective agents. In this work, we created new analogs of two established but non-selective HDAC inhibitors. We decorated the central linker chains of the molecules with specifically positioned fluorine atoms in order to control the molecular conformations. The fluorinated analogs were screened against a panel of 11 HDAC isoforms, and minor differences in isoform selectivity patterns were observed.

scholarly journals Synergism of Heat Shock Protein 90 and Histone Deacetylase Inhibitors in Synovial Sarcoma

Sarcoma ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Anne Nguyen ◽  
Le Su ◽  
Belinda Campbell ◽  
Neal M. Poulin ◽  
Torsten O. Nielsen
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Synovial Sarcoma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Therapeutic Benefit ◽  
Multiple Time

Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-κB, potentially limiting therapeutic benefit. As 17-AAG inhibits activators of NF-κB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-κB activation. In our assays, adding 17-AAG blocks NF-κB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-κB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-κB synergize with HDAC inhibitors against synovial sarcoma.

scholarly journals Design, synthesis and evaluation of belinostat analogs as histone deacetylase inhibitors

2019 ◽  
Vol 11 (21) ◽  
pp. 2765-2778
Author(s):  
Jie-Huan Zhang ◽  
Madhusoodanan Mottamal ◽  
Hai-Shan Jin ◽  
Shanchun Guo ◽  
Yan Gu ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Compound ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Antitumor Therapy ◽  
Design Synthesis ◽  
Inhibitory Activities ◽  
Antiproliferative Activities

Aim: Histone deacetylase (HDAC) is an attractive target for antitumor therapy. Therefore, the development of novel HDAC inhibitors is warranted. Materials & methods: A series of HDAC inhibitors based on N-hydroxycinnamamide fragment was designed as the clinically used belinostat analog using amide as the connecting unit. All target compounds were evaluated for their in vitro HDAC inhibitory activities and some selected compounds were tested for their antiproliferative activities. Conclusion: Among them, compound 7e showed an IC50 value of 11.5 nM in inhibiting the HDAC in a pan-HDAC assay, being the most active compound of the series.

scholarly journals Resistance to histone deacetylase inhibitors confers hypersensitivity to oncolytic reovirus therapy

2020 ◽  
Vol 4 (20) ◽  
pp. 5297-5310
Author(s):  
Shariful Islam ◽  
Claudia M. Espitia ◽  
Daniel O. Persky ◽  
Jennifer S. Carew ◽  
Steffan T. Nawrocki
Keyword(s):  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Histone Deacetylase Inhibitors ◽  
Molecular Mechanisms ◽  
Hdac Inhibitors ◽  
Cross Resistance ◽  
Drug Resistant ◽  
In Vivo Models ◽  
Clinical Issue ◽  
Resistant Cells

Abstract Despite the promising antilymphoma activity of histone deacetylase (HDAC) inhibitors as a drug class, resistance is a significant clinical issue. Elucidating the molecular mechanisms driving HDAC inhibitor resistance and/or the specific targets that are altered in drug-resistant cells may facilitate the development of strategies that overcome drug resistance and are more effective for refractory patients. We generated novel T-cell lymphoma (TCL) cell line models of acquired resistance to the HDAC inhibitor belinostat to identify potential effective therapies. Belinostat-resistant cells displayed significant cross-resistance to other HDAC inhibitors including romidepsin, panobinostat, and vorinostat. Consistent with a lack of sensitivity to HDAC inhibitors, the resistant cells failed to induce increased acetylated histones. Drug-resistant cells featured significantly decreased expression of the key antiviral mediators IRF1 and STAT1. On the basis of these findings, we investigated the efficacy of the clinical formulation of reovirus (Reolysin) in parental and drug-resistant models. Our investigation revealed that HDAC inhibitor–resistant cells displayed enhanced vulnerability to reovirus replication and cell death in both in vitro and in vivo models compared with their parental counterparts. Importantly, Reolysin also significantly increased the antilymphoma activity of belinostat in HDAC inhibitor–resistant cells. Our data demonstrate that Reolysin alone or in combination with belinostat is a novel therapeutic strategy to treat TCL patients who develop resistance to HDAC inhibitors.

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.

scholarly journals Histone Deacetylase Inhibitors Down-Regulate bcl-2 Expression and Induce Apoptosis in t(14;18) Lymphomas

2005 ◽  
Vol 25 (5) ◽  
pp. 1608-1619 ◽  
Author(s):  
Hong Duan ◽  
Caroline A. Heckman ◽  
Linda M. Boxer
Keyword(s):  
Cell Cycle ◽  
Histone Deacetylase ◽  
Chromatin Immunoprecipitation ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Agents ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Transcriptional Level ◽  
Cycle Arrest ◽  
Induced Apoptosis

ABSTRACT Histone deacetylase (HDAC) inhibitors are promising antitumor agents, but they have not been extensively explored in B-cell lymphomas. Many of these lymphomas have the t(14;18) translocation, which results in increased bcl-2 expression and resistance to apoptosis. In this study, we examined the effects of two structurally different HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB), on the cell cycle, apoptosis, and bcl-2 expression in t(14;18) lymphoma cells. We found that in addition to potent cell cycle arrest, TSA and NaB also dramatically induced apoptosis and down-regulated bcl-2 expression, and overexpression of bcl-2 inhibited TSA-induced apoptosis. The repression of bcl-2 by TSA occurred at the transcriptional level. Western blot analysis and quantitative chromatin immunoprecipitation (ChIP) assay showed that even though HDAC inhibitors increased overall acetylation of histones, localized histone H3 deacetylation occurred at both bcl-2 promoters. TSA treatment increased the acetylation of the transcription factors Sp1 and C/EBPα and decreased their binding as well as the binding of CBP and HDAC2 to the bcl-2 promoters. Mutation of Sp1 and C/EBPα binding sites reduced the TSA-induced repression of bcl-2 promoter activity. This study provides a mechanistic rationale for the use of HDAC inhibitors in the treatment of human t(14;18) lymphomas.

scholarly journals Histone Deacetylase Inhibitors: Synthesis of Tetrapeptide Analogue SAHA/TPX

2011 ◽  
Vol 8 (s1) ◽  
pp. S79-S84
Author(s):  
Lynda Ekou ◽  
Tchirioua Ekou ◽  
Isabelle Opalinski ◽  
Jean Pierre Gesson
Keyword(s):  
Clinical Trial ◽  
Cancer Therapy ◽  
Phase I ◽  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Growth Arrest ◽  
Suberoylanilide Hydroxamic Acid ◽  
Specific Inhibitors

The inhibition of HDAC (histone deacetylase) activity by specific inhibitors induces growth arrest, differentiation and apoptosis of transformed or several cancer cells. Some of these inhibitors are in clinical trial at phase I or phase II. The discovery and development of specific HDAC inhibitors are helpful for cancer therapy. In this paper we describe the synthesis of simple inhibitorBhybrid analogue suberoylanilide hydroxamic acid (SAHA), trapoxinB(TPX B) in as little as five steps. This compound is interesting lead for the design of potent inhibitors of histone deacetylase.

scholarly journals Histone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Antitumor Activities

ChemMedChem ◽  
2013 ◽  
Vol 9 (3) ◽  
pp. 638-648 ◽  
Author(s):  
Lei Zhang ◽  
Yingjie Zhang ◽  
C. James Chou ◽  
Elizabeth S. Inks ◽  
Xuejian Wang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Antitumor Activities ◽  
Enzymatic Inhibition

scholarly journals Histone deacetylase inhibitors suppress IL-2–mediated gene expression prior to induction of apoptosis

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1490-1495 ◽  
Author(s):  
Yuko Koyama ◽  
Masaaki Adachi ◽  
Masuo Sekiya ◽  
Mutsuhiro Takekawa ◽  
Kohzoh Imai
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
K562 Cells ◽  
Histone Hyperacetylation ◽  
Induced Apoptosis ◽  
Do So

Histone deacetylase (HDAC) inhibitors can induce transcriptional activation of a number of genes and induce cellular differentiation as histone acetylation levels increase. Although these inhibitors induce apoptosis in several cell lines, the precise mechanism by which they do so remains obscure. This study shows that HDAC inhibitors, sodium butyrate and trichostatin A (TSA), abrogate interleukin (IL)-2–mediated gene expression in IL-2–dependent cells. The HDAC inhibitors readily induced apoptosis in IL-2–dependent ILT-Mat cells and BAF-B03 transfectants expressing the IL-2 receptor βc chain, whereas they induced far less apoptosis in cytokine-independent K562 cells. However, these inhibitors similarly increased acetylation levels of histones in both cells. Although histone hyperacetylation is believed to lead to transcriptional activation, the results showed an abrogation of IL-2–mediated induction of c-myc,bag-1, and LC-PTP gene expression. This observed abrogation of gene expression occurred prior to phosphatidylserine externalization, a process that occurs in early apoptotic cells. Considering the biologic role played by IL-2–mediated gene expression in cell survival, these data suggest that its abrogation may contribute to the apoptotic process induced by HDAC inhibitors.

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