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Pharmaceuticals
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Advances in HDAC Inhibitors
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Advances in HDAC Inhibitors

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

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 10631

Special Issue Editors

Prof. Dr. Chung Man Chin

E-Mail Website
Guest Editor
1. School of Pharmaceutical Science, State University of São Paulo (UNESP), São Paulo, Brazil
2. School of Medicine, Union of the Colleges of the Great Lakes (UNILAGO), SJRP, São Paulo, Brazil
Interests: new drugs; drug design; drug discovery; infectious disease; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Jean Leandro Dos Santos

E-Mail Website
Guest Editor
School of Pharmaceutical Science, State University of São Paulo (UNESP), São Paulo, Brazil
Interests: new drugs; drug design; drug discovery; infectious disease; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It has been more than 32 years since the first histone deacetylase inhibitor, the natural product trichostatin A, was described. Despite the advances in drug design that allow selectively targeting the distinct isoforms, only a few drugs have been approved by regulatory agencies worldwide. In humans, histone deacetylase (HDAC) enzymes are comprised of 18 enzymes divided into two mains families: zinc-dependent metalloenzymes (HDAC1-11) and those dependent on NAD+ as a co-factor, known as sirtuins (1-7). Currently, medicinal chemistry approaches aiming to identify synthetic and natural-based HDAC inhibitors have been described in the literature. Although commonly focused on cancer, other indications such as epilepsy, diabetes, pain, neurodegenerative disorders, infectious diseases, rare diseases (e.g., sickle cell disease, Duchenne and Becker muscular dystrophy), etc., have gained attention not only for monotherapy but also for combined therapy. In this Special Issue, we will highlight the recent advances and progress made in the development of HDAC inhibitors from the perspective of medicinal chemistry. Clinical studies describing the advances in HDAC inhibitors are also welcome.

Prof. Dr. Chung Man Chin
Prof. Dr. Jean Leandro Dos Santos
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • epigenetics
  • histone deacetylase
  • HDAC inhibitors
  • new drugs

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Published Papers (4 papers)

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Research

16 pages, 2772 KiB  
Article
Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy
by Fabian B. Kraft, Maria Hanl, Felix Feller, Linda Schäker-Hübner and Finn K. Hansen
Pharmaceuticals 2023, 16(3), 356; https://doi.org/10.3390/ph16030356 - 25 Feb 2023
Cited by 7 | Viewed by 2351
Abstract
Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide [...] Read more.
Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (I) and VK1 (II). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I. In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I. Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi. Full article
(This article belongs to the Special Issue Advances in HDAC Inhibitors)
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16 pages, 2866 KiB  
Article
A Class I HDAC Inhibitor BG45 Alleviates Cognitive Impairment through the CaMKII/ITPKA/Ca2+ Signaling Pathway
by Jingyun Liu, Chenghong Zhang, Jiale Wang, Yufei Huang, Di Shen, Yingqiu Hu, Haiying Chu, Xuebin Yu, Liyuan Zhang and Haiying Ma
Pharmaceuticals 2022, 15(12), 1481; https://doi.org/10.3390/ph15121481 - 28 Nov 2022
Cited by 2 | Viewed by 2230
Abstract
Alzheimer’s disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) [...] Read more.
Alzheimer’s disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins was investigated in primary neurons from APP/PS1 transgenic mice. The results showed that BG45 can upregulate the expression of synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons. In vivo, the APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with BG45 (30 mg/kg) daily for 12 days. Behavioral testing of BG45-treated APP/PS1 mice showed improvements in learning and memory. BG45 can alleviate damage to the dendritic spine and reduce the deposition of Aβ. Similar to the in vitro results, synapse-related proteins in the prefrontal cortex were increased after BG45 treatment. Proteomic analysis results highlighted the differences in the biological processes of energy metabolism and calmodulin regulation in APP/PS1 mice with or without BG45 treatment. Further verification demonstrated that the effect of BG45 on synapses and learning and memory may involve the CaMKII/ITPKA/Ca2+ pathway. These results suggest that class I HDACI BG45 might be a promising drug for the early clinical treatment of AD. Full article
(This article belongs to the Special Issue Advances in HDAC Inhibitors)
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20 pages, 4817 KiB  
Article
High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma
by Harsimran Kaur Garcha, Nabanita Nawar, Helena Sorger, Fettah Erdogan, Myint Myat Khine Aung, Abootaleb Sedighi, Pimyupa Manaswiyoungkul, Hyuk-Soo Seo, Susann Schönefeldt, Daniel Pölöske, Sirano Dhe-Paganon, Heidi A. Neubauer, Satu M. Mustjoki, Marco Herling, Elvin D. de Araujo, Richard Moriggl and Patrick T. Gunning
Pharmaceuticals 2022, 15(11), 1321; https://doi.org/10.3390/ph15111321 - 26 Oct 2022
Viewed by 3113
Abstract
NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This [...] Read more.
NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL through a second-generation inhibitor NN-429. With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies. Full article
(This article belongs to the Special Issue Advances in HDAC Inhibitors)
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18 pages, 2928 KiB  
Communication
Optimization of Resveratrol Used as a Scaffold to Design Histone Deacetylase (HDAC-1 and HDAC-2) Inhibitors
by Beatriz Silva Urias, Aline Renata Pavan, Gabriela Ribeiro Albuquerque, Igor Muccilo Prokopczyk, Tânia Mara Ferreira Alves, Thais Regina Ferreira de Melo, Geraldo Rodrigues Sartori, João Hermínio Martins da Silva, Chung Man Chin and Jean Leandro Dos Santos
Pharmaceuticals 2022, 15(10), 1260; https://doi.org/10.3390/ph15101260 - 13 Oct 2022
Cited by 7 | Viewed by 2309
Abstract
Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. [...] Read more.
Histone deacetylases (HDAC) are epigenetic enzymes responsible for repressing gene expression through the deacetylation of histone lysine residues. Therefore, inhibition of HDACs has become an interesting approach for the treatment of several diseases, including cancer, hematology, neurodegenerative, immune diseases, bacterial infections, and more. Resveratrol (RVT) has pleiotropic effects, including pan-inhibition of HDAC isoforms; however, its ability to interfere with membranes requires additional optimization to eliminate nonspecific and off-target effects. Thus, to explore RVT as a scaffold, we designed a series of novel HDAC-1 and -2 inhibitors containing the 2-aminobenzamide subunit. Using molecular modeling, all compounds, except unsaturated compounds (4) and (7), exhibited a similar mode of interaction at the active sites of HDAC 1 and 2. The docking score values obtained from the study ranged from −12.780 to −10.967 Kcal/mol. All compounds were synthesized, with overall yields ranging from 33% to 67.3%. In an initial screening, compounds (4), (5), (7), and (20)–(26), showed enzymatic inhibitory effects ranging from 1 to 96% and 6 to 93% against HDAC-1 and HDAC-2, respectively. Compound (5), the most promising HDAC inhibitor in this series, was selected for IC50 assays, resulting in IC50 values of 0.44 µM and 0.37 µM against HDAC-1 and HDAC-2, respectively. In a panel of selectivity against HDACs 3–11, compound (5) presented selectivity towards Class I, mainly HDAC-1, 2, and 3. All compounds exhibited suitable physicochemical and ADMET properties as determined using in silico simulations. In conclusion, the optimization of the RVT structure allows the design of selective HDAC inhibitors, mainly targeting HDAC-1 and HDAC-2 isoforms. Full article
(This article belongs to the Special Issue Advances in HDAC Inhibitors)
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