scholarly journals Histone Deacetylase 11 is an ε-N-Myristoyllysine Hydrolase

2017 ◽  
Author(s):  
Carlos Moreno-Yruela ◽  
Iacopo Galleano ◽  
Andreas S. Madsen ◽  
Christian A. Olsen
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Biological Function ◽  
Hdac Inhibitors ◽  
The Other ◽  
Chemical Probes ◽  
Chain Acyl ◽  
Selective Chemical ◽  
Approved Drugs ◽  
Long Chain

SUMMARYHistone deacetylase (HDAC) enzymes are important regulators of diverse biological function, including gene expression, rendering them potential targets for intervention in a number of diseases, with a handful of compounds approved for treatment of certain hematologic cancers. Among the human zinc-dependent HDACs, the most recently discovered member, HDAC11, is the only member assigned to subclass IV, the smallest protein, and the least well understood with regards to biological function. Here we show that HDAC11 cleaves long chain acyl modifications on lysine side chains with remarkable efficiency compared to acetyl groups. We further show that several common types of HDAC inhibitors, including the approved drugs romidepsin and vorinostat, do not inhibit this enzymatic activity. Macrocyclic hydroxamic acid-containing peptides, on the other hand, potently inhibit HDAC11 demyristoylation activity. These findings should be taken carefully into consideration in future investigations of the biological function of HDAC11 and will serve as a foundation for the development of selective chemical probes targeting HDAC11.

Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation

2021 ◽  
Author(s):  
Raphael R. Steimbach ◽  
Corey J. Herbst-Gervasoni ◽  
Glynis Klinke ◽  
Magalie Géraldy ◽  
Gergely Tihanyi ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Target Engagement ◽  
Target Validation ◽  
Chemical Probes ◽  
Combination Cancer Therapy ◽  
Selective Chemical ◽  
First Time ◽  
Double Digit ◽  
Novel Therapeutic ◽  
Thermal Shift

We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded DKFZ-748, which has a double-digit nanomolar IC50 against HDAC10 in cells and >500-fold selectivity over the closest relative HDAC6 as well as the Class I enzymes (HDAC1, 2, 3, 8). Potency of our aza-SAHA derivatives is rationalized with HDAC10 co-crystal structures and demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a poly-amine deacetylase. Selective HDAC10 chemical probes provide a valuable pharmacological tool for target validation and will enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines. HDAC10-selective aza-SAHA derivatives are not cytotoxic, which opens the doors to novel therapeutic applications as immunomodulators or in combination cancer therapy.

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.

Discovery, Synthesis, and Pharmacological Evaluation of Spiropiperidine Hydroxamic Acid Based Derivatives as Structurally Novel Histone Deacetylase (HDAC) Inhibitors

2011 ◽  
Vol 54 (8) ◽  
pp. 3051-3064 ◽  
Author(s):  
Mario Varasi ◽  
Florian Thaler ◽  
Agnese Abate ◽  
Chiara Bigogno ◽  
Roberto Boggio ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Pharmacological Evaluation

ITF2357, a Novel Histone Deacetylase Inhibitor, Demonstrates Significant Apoptotic Activity Against Human Multiple Myeloma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4791-4791
Author(s):  
Michael Kline ◽  
Kathleen A. Donovan ◽  
John A. Lust
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Hydroxamic Acid ◽  
Stromal Cell ◽  
Hdac Inhibitors ◽  
Annexin V ◽  
Myeloma Cells

Abstract We have evaluated the efficacy of a novel hydroxamic acid-derived histone deacetylase (HDAC) inhibitor, ITF2357, to promote cell death in multiple myeloma (MM) cells. HDAC inhibitors, which promote histone hyperacetylation and increase gene expression, have been evaluated as candidate agents for combating malignancies because they impact the expression of genes related to proliferation, differentiation, and survival. Exposure of MM cell lines to 1 micromolar ITF2357 led to dramatically increased levels of histone acetylation at 4 hours and 8 hours by Western analysis. Sub-micromolar concentrations of ITF2357 promoted time- and concentration-dependent cell death in MM cell lines. Using 500 nM ITF2357, a concentration potentially achievable in vivo, viability of KAS-6/1 IL-6 dependent myeloma cells was reduced to 28% of control at 24 hrs and 2% of control at 48 hours (Figure 1). In contrast, viability of normal PBMCs was 100% at 24 hours and 80% at 48 hours (Figure 2). U266 and 8226 myeloma cells were found to be sensitive to ITF-2357 in a similar fashion with U266 being least sensitive. Cell death proceeded via apoptosis as measured using Annexin V/propidium iodide staining. ITF 2357 was superior to suberoylanilide hydroxamic acid (SAHA) at inhibition of stromal cell IL-6 production. IL-1beta (10 pg/ml) was used to stimulate bone marrow stromal cell IL-6 production (105 ng/ml) after 48 hours. Concentration of ITF2357:Stromal Cell IL-6 production after 48 hours were as follows - 10 nM: 78 ng/ml; 100 nM: 79 ng/ml; 1000 nM; 32 ng/ml. SAHA at similar concentrations showed no significant decrease in stromal cell IL-6 production compared with the no drug control. In summary, ITF2357 induces significant myeloma cell apoptosis and can inhibit stromal cell IL-6 production. It represents an attractive therapeutic candidate for MM clinical trials. Figure Figure Figure Figure

scholarly journals Histone deacetylase inhibitors are potent inducers of gene expression in latent EBV and sensitize lymphoma cells to nucleoside antiviral agents

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 1008-1017 ◽  
Author(s):  
Sajal K. Ghosh ◽  
Susan P. Perrine ◽  
Robert M. Williams ◽  
Douglas V. Faller
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Hydroxamic Acid ◽  
Antiviral Agents ◽  
Hdac Inhibitors ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Lymphoma Cells

AbstractInduction of EBV lytic-phase gene expression, combined with exposure to an antiherpes viral drug, represents a promising targeted therapeutic approach to EBV-associated lymphomas. Short-chain fatty acids or certain chemotherapeutics have been used to induce EBV lytic-phase gene expression in cultured cells and mouse models, but these studies generally have not translated into clinical application. The recent success of a clinical trial with the pan-histone deacetylase (pan-HDAC) inhibitor arginine butyrate and the antiherpes viral drug ganciclovir in the treatment of EBV lymphomas prompted us to investigate the potential of several HDAC inhibitors, including some new, highly potent compounds, to sensitize EBV+ human lymphoma cells to antiviral agents in vitro. Our study included short-chain fatty acids (sodium butyrate and valproic acid); hydroxamic acids (oxamflatin, Scriptaid, suberoyl anilide hydroxamic acid, panobinostat [LBH589], and belinostat [PXD101]); the benzamide MS275; the cyclic tetrapeptide apicidin; and the recently discovered HDAC inhibitor largazole. With the exception of suberoyl anilide hydroxamic acid and PXD101, all of the other HDAC inhibitors effectively sensitized EBV+ lymphoma cells to ganciclovir. LBH589, MS275, and largazole were effective at nanomolar concentrations and were 104 to 105 times more potent than butyrate. The effectiveness and potency of these HDAC inhibitors make them potentially applicable as sensitizers to antivirals for the treatment of EBV-associated lymphomas.

Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors

2006 ◽  
Vol 14 (22) ◽  
pp. 7625-7651 ◽  
Author(s):  
Chihiro Shinji ◽  
Satoko Maeda ◽  
Keisuke Imai ◽  
Minoru Yoshida ◽  
Yuichi Hashimoto ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Design Synthesis ◽  
Cyclic Amide ◽  
Hydroxamic Acid Derivatives

An In-Silico Approach to Evaluate the Inhibitory Potency of Selected Hydroxamic Acid Derivatives on Zinc-Dependent Histone Deacetylase Enzyme

2021 ◽  
Vol 20 (06) ◽  
pp. 603-618
Author(s):  
R. Dushanan ◽  
S. Weerasinghe ◽  
D. P. Dissanayake ◽  
R. Senthilnithy
Keyword(s):  
Free Energy ◽  
Interaction Energy ◽  
Histone Deacetylase ◽  
In Silico ◽  
Hydroxamic Acid ◽  
Binding Free Energy ◽  
Hdac Inhibitors ◽  
Drug Binding ◽  
The Body ◽  
Energy Formula

Histone deacetylase (HDAC) enzymes modify the histone by removing the acetyl group from the lysine residues, known as histone deacetylation. HDACs have been involved in altering gene expressions, resulting in cancer cells in the body. This study focuses on HDAC inhibitors’ impact on histone deacetylase-like protein (HDLP) stability through computational techniques. Molecular dynamics (MD) analyses were used to examine the atomic-level description of drug binding sites and how the HDAC inhibitors change the HDLP enzyme environment. In this study, two hydroxamic acid-derived inhibitors, such as [Formula: see text]-Carboxycinnamic acid bis-hydroxamide (CBHA) and scriptaid (GCK1026), were selected to examine the inhibition ability in terms with suberanilohydroxamic acid (SAHA) as a reference drug. The crystal structure of the HDLP was downloaded from the Protein Data Bank. The structures of inhibitors were optimized using the G09W package. Docking studies were done by AutoDock-Vina, and the resultant complex was used to initiate MD studies. The trajectories obtained from MD simulation were used to perform the structural analysis. Root-mean-square deviation (RMSD), radius of gyration, hydrogen bond, binding free energy and interaction energy studies revealed that the stability of HDLP-SAHA and HDLP-CBHA is higher than the free HDLP enzyme. The HDLP-CBHA complex shows an increased number of hydrogen bonds (5), high MM-PBSA binding free energy ([Formula: see text][Formula: see text]kJ/mol), high interaction energy ([Formula: see text][Formula: see text]kJ/mol), and an increased number of alpha-helical amino acids (130) compared with HDLP-SAHA. It concluded that the CBHA has the relatively same potential as SAHA to inhibit the HDLP. Consequently, the use of CBHA in clinical application is recommended through this in-silico method.

scholarly journals Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Can Mediate Neuroprotection Independent of HDAC Inhibition

2014 ◽  
Vol 34 (43) ◽  
pp. 14328-14337 ◽  
Author(s):  
S. F. Sleiman ◽  
D. E. Olson ◽  
M. W. Bourassa ◽  
S. S. Karuppagounder ◽  
Y.-L. Zhang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Hdac Inhibitors ◽  
Hdac Inhibition

Induction of Human γ Globin Gene Expression by Histone Deacetylase Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1583-1583
Author(s):  
Hua Cao
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Hydroxamic Acid ◽  
Globin Gene ◽  
Hdac Inhibitors ◽  
Fetal Hemoglobin ◽  
Erythroid Progenitor ◽  
Globin Gene Expression ◽  
Hydroxamic Acid Derivatives

In previous studies we have showed that HDAC inhibitors including hydroxamic acid derivatives of short chain fatty acids butyryl hydroxamate, propionyl hydroxamate, subericbis hydroxamic acid (SBHA), and suberoylanilide hydroxamic acid (SAHA), are potent inducers of γ globin gene expression in in vitro luciferase assays and in cultures of human adult erythroid progenitor cells. In this present study, we used μLCR Aγ transgenic mice to test whether these compounds can also induce γ gene expression in vivo. We found that in addition to γ gene induction these compounds have considerable erythropoiesis activity. Thus, Propionyl and butyryl hydroxamate increased reticulocytes of mice by 71% and 139%, the in vivo BFUe counts by 75% and 51% and the in vivo γ gene expression by 33.9% and 71% respectively. SBHA and SAHA had no erythropoietic activity in vivo. We conclude that Hydroxamic acid derivatives can stimulate both the in vivo erythropoiesis and fetal globin production in a thalassemic murine model. Cyclic depsipeptide FK228 is a highly potent histone deacetylase inhibitor, currently in clinical trials in cancer patients. We investigated whether FK228 also functions as inducer of human γ globin gene expression and compared Hb F induction by FK228 to that of four other HDAC inhibitors, including hydroxamic acids (TSA), synthetic benzamides (MS-275), and two cyclic tetrapeptides, Apicidin and HC-Toxin. Our results showed that FK228 is the most potent fetal hemoglobin inducer among all the HDAC inhibitors tested in our laboratory. In a concentration of 0.84 nanomolar, FK228 induces γ gene promoter activity in the dual luciferase assay by 7.81 fold. In the human erythroid progenitor cell cultures it increases the levels of γ mRNA by 8.48 fold in a concentration of 0.143 nM. In contrast, fetal hemoglobin induction by other HDAC inhibitors is achieved in concentrations that are 100 to 1000 fold higher. We conclude that FK228 is a promising compound for induction of Hb F in patients with sickle cell disease and thalassemia.

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