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Drug Insight: Histone Deacetylase (HDAC) Inhibitors
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Drug Insight: Histone Deacetylase (HDAC) Inhibitors

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (18 February 2022) | Viewed by 24140

Special Issue Editor

Prof. Dr. Carlos Alberto Manssour Fraga

E-Mail Website
Guest Editor
1. Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
2. Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, Brazil
Interests: medicinal chemistry; drug design and discovery; multitarget drugs for neurodegenerative diseases; use of privileged structures to design new epigenetic drug candidates; discovery of new kinase inhibitors for chronic inflammatory diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since epigenetics emerged in the 21st century as an important branch of biological sciences, many efforts have been made to exploit epigenetic targets in drug discovery programs worldwide. Among the proteins involved in epigenetic changes, categorized as readers, writers, and erasers, histone deacetylases (HDACs) occupy a prominent position in the search for novel drug candidates as monotherapy or in the design of multitarget prototypes. These enzymes are associated with the regulation of the acetylation pattern of a wide range of nuclear and cytoplasmatic proteins through their ability to hydrolyze the acetyl groups of lysine residues, which results in important changes in their 3D structures. Nowadays it is well known that deregulated HDAC activity can be found in many pathological states such as cancer, neurodegenerative diseases, and chronic inflammatory diseases.

Although four HDAC pan-inhibitors have been approved by the FDA for the treatment of hematological tumors, it clearly important to discover isoform-selective HDAC inhibitors to avoid side-effects and to allow the expansion of the use of this therapeutic class in the treatment of different diseases. Therefore, this Special Issue has the aim to invite both reviews and original articles describing structural aspects for the selective inhibition of HDAC isoforms and the discovery of new HDAC inhibitors, as well as their therapeutic applications.

Prof. Dr. Carlos Manssour Fraga
Guest Editor

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Keywords

  • histone deacetylase
  • HDAC inhibitor
  • isoform-selective HDAC inhibitor
  • HDAC6 inhibitor
  • multitarget HDAC inhibitor
  • epigenetics
  • cancer
  • neurodegenerative disease
  • inflammatory disease
  • Alzheimer’s disease

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Published Papers (8 papers)

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Research

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30 pages, 4739 KiB  
Article
Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain
by Oliver Clauß, Linda Schäker-Hübner, Barbara Wenzel, Magali Toussaint, Winnie Deuther-Conrad, Daniel Gündel, Rodrigo Teodoro, Sladjana Dukić-Stefanović, Friedrich-Alexander Ludwig, Klaus Kopka, Peter Brust, Finn K. Hansen and Matthias Scheunemann
Pharmaceuticals 2022, 15(3), 324; https://doi.org/10.3390/ph15030324 - 8 Mar 2022
Viewed by 3746
Abstract
The degree of acetylation of lysine residues on histones influences the accessibility of DNA and, furthermore, the gene expression. Histone deacetylases (HDACs) are overexpressed in various tumour diseases, resulting in the interest in HDAC inhibitors for cancer therapy. The aim of this work [...] Read more.
The degree of acetylation of lysine residues on histones influences the accessibility of DNA and, furthermore, the gene expression. Histone deacetylases (HDACs) are overexpressed in various tumour diseases, resulting in the interest in HDAC inhibitors for cancer therapy. The aim of this work is the development of a novel 18F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). BA3, exhibiting high inhibitory potency for HDAC1 (IC50 = 4.8 nM) and HDAC2 (IC50 = 39.9 nM), and specificity towards HDAC3 and HDAC6 (specificity ratios >230 and >2080, respectively), was selected for radiofluorination. The two-step one-pot radiosynthesis of [18F]BA3 was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [18F]BA3 resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (n = 5, EOS). For the characterization of BA3, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of BA3, whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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20 pages, 4865 KiB  
Article
Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor
by Nils Goehringer, Yayi Peng, Bianca Nitzsche, Hannah Biermann, Rohan Pradhan, Rainer Schobert, Marco Herling, Michael Höpfner and Bernhard Biersack
Pharmaceuticals 2021, 14(12), 1319; https://doi.org/10.3390/ph14121319 - 17 Dec 2021
Cited by 7 | Viewed by 2933
Abstract
The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising [...] Read more.
The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC50 values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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13 pages, 1381 KiB  
Article
HDAC4 Is Indispensable for Reduced Slow Myosin Expression at the Early Stage of Hindlimb Unloading in Rat Soleus Muscle
by Inna I. Paramonova, Natalia A. Vilchinskaya and Boris S. Shenkman
Pharmaceuticals 2021, 14(11), 1167; https://doi.org/10.3390/ph14111167 - 16 Nov 2021
Cited by 5 | Viewed by 1928
Abstract
It is well known that reduced contractile activity of the main postural soleus muscle during long-term bedrest, immobilization, hindlimb unloading, and space flight leads to increased expression of fast isoforms and decreased expression of the slow isoform of myosin heavy chain (MyHC). The [...] Read more.
It is well known that reduced contractile activity of the main postural soleus muscle during long-term bedrest, immobilization, hindlimb unloading, and space flight leads to increased expression of fast isoforms and decreased expression of the slow isoform of myosin heavy chain (MyHC). The signaling cascade such as HDAC4/MEF2-D pathway is well-known to take part in regulating MyHC I gene expression. Earlier, we found a significant increase of HDAC4 in myonuclei due to AMPK dephosphorylation during 24 h of hindlimb unloading via hindlimb suspension (HU) and it had a significant impact on the expression of MyHC isoforms in rat soleus causing a decrease in MyHC I(β) pre-mRNA and mRNA expression as well as MyHC IIa mRNA expression. We hypothesized that dephosphorylated HDAC4 translocates into the nuclei and can lead to a reduced expression of slow MyHC. To test this hypothesis, Wistar rats were treated with HDAC4 inhibitor (Tasquinimod) for 7 days before HU as well as during 24 h of HU. We discovered that Tasquinimod treatment prevented a decrease in pre-mRNA expression of MyHC I. Furthermore, 24 h of hindlimb suspension resulted in HDAC4 nuclear accumulation of rat soleus but Tasquinimod pretreatment prevented this accumulation. The results of the study indicate that HDAC4 after 24 h of HU had a significant impact on the precursor MyHC I mRNA expression in rat soleus. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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30 pages, 4645 KiB  
Article
Mechanistic Insights into Binding of Ligands with Thiazolidinedione Warhead to Human Histone Deacetylase 4
by Markus Schweipert, Niklas Jänsch, Neha Upadhyay, Kalpana Tilekar, Ewelina Wozny, Sidra Basheer, Eva Wurster, Marlene Müller, Ramaa C S and Franz-Josef Meyer-Almes
Pharmaceuticals 2021, 14(10), 1032; https://doi.org/10.3390/ph14101032 - 11 Oct 2021
Cited by 8 | Viewed by 2227
Abstract
Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure [...] Read more.
Recently, we have reported that non-hydroxamate thiazolidinedione (TZD) analogs are capable of inhibiting human deacetylase 4 (HDAC4). This study aims at the dissection of the molecular determinants and kinetics of the molecular recognition of TZD ligands by HDAC4. For this purpose, a structure activity relationship analysis of 225 analogs was combined with a comprehensive study of the enzyme and binding kinetics of a variety of HDAC4 mutant variants. The experimental data were rationalized by docking to the two major conformations of HDAC4. TZD ligands are competitive inhibitors and bind via a two-step mechanism involving principal molecular recognition and induced fit. The residence time of 24 g is (34 ± 3) min and thus much larger than that of the canonical pan-HDAC inhibitor SAHA ((5 ± 2) min). Importantly, the binding kinetics can be tuned by varying the structure of the CAP group. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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18 pages, 4772 KiB  
Article
Anti-Proliferative, Anti-Angiogenic and Safety Profiles of Novel HDAC Inhibitors for the Treatment of Metastatic Castration-Resistant Prostate Cancer
by Zohaib Rana, Sarah Diermeier, Fearghal P. Walsh, Muhammad Hanif, Christian G. Hartinger and Rhonda J. Rosengren
Pharmaceuticals 2021, 14(10), 1020; https://doi.org/10.3390/ph14101020 - 4 Oct 2021
Cited by 7 | Viewed by 2579
Abstract
Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that [...] Read more.
Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that novel HDAC inhibitors (Jazz90 (N1-hydroxy-N8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide) and Jazz167 ([chlorido(η5-pentamethylcyclopentadieny[1–4](N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2N,S)phenyl)octanediamide)rhodium(III)] chloride) had a higher cancer-to-normal-cell selectivity and superior anti-angiogenic effects in CRPC (PC3) cells than SAHA. Thus, this study aimed to further investigate the efficacy and toxicity of these compounds. HUVEC tube formation assays revealed that Jazz90 and Jazz167 significantly reduced meshes and segment lengths in the range of 55–88 and 43–64%, respectively. However, Jazz90 and Jazz167 did not affect the expression of epithelial-to-mesenchymal transitioning markers E-cadherin and vimentin. Jazz90 and Jazz167 significantly inhibited the growth of PC3 and DU145 spheroids and reduced PC3 spheroid branching. Jazz90 and Jazz167 (25, 50 and 75 mg/kg/day orally for 21 days) were non-toxic in male BALB/c mice. The efficacy and safety of these compounds demonstrate their potential for further in vivo studies in CRPC models. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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17 pages, 2165 KiB  
Article
Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues
by Bartosz Bieszczad, Damian Garbicz, Marta Świtalska, Marta K. Dudek, Dawid Warszycki, Joanna Wietrzyk, Elżbieta Grzesiuk and Adam Mieczkowski
Pharmaceuticals 2021, 14(9), 851; https://doi.org/10.3390/ph14090851 - 26 Aug 2021
Cited by 6 | Viewed by 3564
Abstract
Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ [...] Read more.
Histone deacetylase (HDAC) inhibitors are a class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that 3 out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one, and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in the lymphoma cell line Daudi, three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumours: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference BALB/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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14 pages, 3756 KiB  
Article
Novel Single Inhibitor of HDAC6/8 and Dual Inhibitor of PI3K/HDAC6 as Potential Alternative Treatments for Prostate Cancer
by Fabiana Sélos Guerra, Daniel Alencar Rodrigues, Carlos Alberto Manssour Fraga and Patricia Dias Fernandes
Pharmaceuticals 2021, 14(5), 387; https://doi.org/10.3390/ph14050387 - 21 Apr 2021
Cited by 9 | Viewed by 2415
Abstract
Background: Prostate cancer is the second most frequently diagnosed malignancy worldwide. Here, the cytotoxic and antimetastatic effects of a new HDAC6/8 inhibitor, LASSBio-1911, and a new dual-PI3K/HDAC6 inhibitor, LASSBio-2208, were evaluated against PC3 prostate cancer cell line. Methods: A MTT assay was used [...] Read more.
Background: Prostate cancer is the second most frequently diagnosed malignancy worldwide. Here, the cytotoxic and antimetastatic effects of a new HDAC6/8 inhibitor, LASSBio-1911, and a new dual-PI3K/HDAC6 inhibitor, LASSBio-2208, were evaluated against PC3 prostate cancer cell line. Methods: A MTT assay was used to assess the cell viability. Annexin V/propidium iodide (PI) was used to detect apoptotic cell death and to analyze the cell cycle distribution. Interleukin 6 (IL-6) levels were measured by ELISA. A cell scratch assay was performed to assess cell migration, and the expression of proteins was estimated by Western blotting. Results: LASSBio-1911 and LASSBio-2208 exert cytotoxic effects against PC3 cells. However, LASSBio-2208 was demonstrated to be more potent than LASSBio-1911. The apoptosis assays showed that both compounds trigger apoptotic processes and cause the arrest of cells in the G2/M phase of the cell cycle. The Western blot analysis revealed that LASSBio-2208 significantly decreased the expression of p-JNK and JAK2. However, both compounds reduced the expression of p-STAT3, IL-6 secretion, and cell migration. Conclusions: LASSBio-1911 and LASSBio-2208 demonstrated significant activity in reducing cell viability and migration. These compounds can be further used as prototypes for the development of new potential anticancer alternative treatments. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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Review

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15 pages, 3862 KiB  
Review
HDAC Inhibitors for the Therapy of Triple Negative Breast Cancer
by Cristina Maccallini, Alessandra Ammazzalorso, Barbara De Filippis, Marialuigia Fantacuzzi, Letizia Giampietro and Rosa Amoroso
Pharmaceuticals 2022, 15(6), 667; https://doi.org/10.3390/ph15060667 - 26 May 2022
Cited by 22 | Viewed by 3269
Abstract
Triple negative breast cancer (TNBC) is an urgent as well as huge medical challenge, which is associated with poor prognosis and responsiveness to chemotherapies. Since epigenetic changes are highly implicated in TNBC tumorigenesis and development, inhibitors of histone deacetylases (HDACIs) could represent a [...] Read more.
Triple negative breast cancer (TNBC) is an urgent as well as huge medical challenge, which is associated with poor prognosis and responsiveness to chemotherapies. Since epigenetic changes are highly implicated in TNBC tumorigenesis and development, inhibitors of histone deacetylases (HDACIs) could represent a promising therapeutic strategy. Although clinical trials involving single HDACIs showed disappointing results against TNBC, recent studies emphasize the high potential impact of HDACIs in controlling TNBC. In addition, encouraging results stem from new compounds designed to obtain isoform selectivity and/or polypharmacological HDAC approach. The present review provides a discussion of the HDACIs pharmacophoric models and of the structural modifications, leading to compounds with a potent activity against TNBC progression. Full article
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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