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

doi:10.1002/cbdv.201900427

Cited by 20 publications

(5 citation statements)

References 64 publications

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“…In general, HDACs are epigenetic regulatory enzymes regulating the acetylation of histone lysine residues and nonhistone proteins and are important mediators of gene expression (F. Yang, Zhao, Hu, Jiang, & Zhang, 2019). In a fungal model, HDACs are shown to collaboratively repress or activate secondary metabolite production (Lan et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Retracted: HDAC2‐mediated proliferation of trophoblast cells requires the miR‐183/FOXA1/IL‐8 signaling pathway

Zhu

Wang

2020

Journal Cellular Physiology

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Pre‐eclampsia (PE) is a major cause of maternal and perinatal death. Previous research has indicated the role of histone deacetylase 2 (HDAC2) in the pathogenesis of PE but the relevant molecular mechanisms are unknown. However, there is hitherto little information concerning the molecular mechanism behind HDAC2 in PE. Herein, we hypothesized that HDAC2 promotes trophoblast cell proliferation and this requires the involvement of microRNA‐183 (miR‐183), forkhead box protein A1 (FOXA1), and interleukin 8 (IL‐8). We collected placental specimens from 30 PE affected and 30 normal pregnant women. HDAC2 and FOXA1 were poorly expressed while miR‐183 and IL‐8 were highly expressed in placental tissues in PE. In vitro, HDAC2 overexpression enhanced the proliferation, migration, and invasion of human trophoblast cells HTR‐8/SVNEO. HDAC2 inhibited the expression of miR‐183 by diminishing H4 acetylation in the miR‐183 promoter region. miR‐183 inhibition by its specific inhibitor increased the expression of FOXA1 and thus enhanced HTR‐8/SVNEO cell proliferation, migration, and invasion. FOXA1, a transcriptional factor, enhanced HTR‐8/SVNEO cell proliferation, migration, and invasion by inhibiting the transcription of IL‐8. We also observed HDAC2 knockdown was lost upon FOXA1 overexpression, suggesting that HDAC2 could promote HTR‐8/SVNEO proliferation, migration, and invasion through the miR‐183/FOXA1/IL‐8 pathway. In summary, the results highlighted the role of the HDAC2/miR‐183/FOXA1/IL‐8 pathway in PE pathogenesis and thus suggest a novel molecular target for PE.

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Section: Introductionmentioning

confidence: 99%

Retracted: HDAC2‐mediated proliferation of trophoblast cells requires the miR‐183/FOXA1/IL‐8 signaling pathway

Zhu

Wang

2020

Journal Cellular Physiology

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“…For instance, by replacing the hydrogen atom (H) at the C2 position of SAHA's hydrophobic long chain with aliphatic or aromatic hydrocarbons, a new analog named C2-R-SAHA was created. This analog has shown the ability to enhance its selectivity for HDAC6 and 8 [147]. Thanks to the molecular docking approach, highly conserved active catalytic regions across all HDAC isoforms were observed, with class I HDAC exhibiting a narrower hydrophobic channel than HDAC6.…”

Section: Isohydroxamic Acidsmentioning

confidence: 99%

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Curcio,

Rocca,

Alcaro

et al. 2024

Pharmaceuticals

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Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

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“…Studies have shown that modifying the hydrophobic long chain of SAHA can enhance its selectivity for HDAC. For instance, substituting the hydrogen atom (H) at the C2 position of the hydrophobic long chain of SAHA with aliphatic or aromatic hydrocarbons resulted in the analog C2-R-SAHA, which effectively improved its selectivity for HDAC6 and 8 (Yang et al, 2020).…”

Section: Sahamentioning

confidence: 99%

Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

Han,

Feng,

et al. 2023

Chem Biol Drug Des

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Epigenetic regulation of genes through posttranslational regulation of proteins is a well‐explored approach for disease treatment, particularly in cancer chemotherapy. Histone deacetylases have shown significant potential as effective drug targets in therapeutic studies aiming to restore epigenetic normality in oncology. Besides their role in modifying histones, histone deacetylases can also catalyze the deacetylation of various nonhistone proteins and participate in the regulation of multiple biological processes. This paper provides a review of the classification, structure, and functional characteristics of the four classes of human histone deacetylases. The increasing abundance of structural information on HDACs has led to the gradual elucidation of structural differences among subgroups and subtypes. This has provided a reasonable explanation for the selectivity of certain HDAC inhibitors. Currently, the US FDA has approved a total of six HDAC inhibitors for marketing, primarily for the treatment of various hematological tumors and a few solid tumors. These inhibitors all have a common pharmacodynamic moiety consisting of three parts: CAP, ZBG, and Linker. In this paper, the structure–effect relationship of HDAC inhibitors is explored by classifying the six HDAC inhibitors into three main groups: isohydroxamic acids, benzamides, and cyclic peptides, based on the type of inhibitor ZBG. However, there are still many questions that need to be answered in this field. In this paper, the structure‐functional characteristics of HDACs and the structural information of the pharmacophore model and enzyme active region of HDAC is are considered, which can help to understand the inhibition mechanism of the compounds as well as the rational design of HDACs. This paper integrates the structural‐functional characteristics of HDACs as well as the pharmacophore model of HDAC is and the structural information of the enzymatic active region, which not only contributes to the understanding of the inhibition mechanism of the compounds, but also provides a basis for the rational design of HDAC inhibitors.

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The Development Process: from SAHA to Hydroxamate HDAC Inhibitors with Branched CAP Region and Linear Linker

Cited by 20 publications

References 64 publications

Retracted: HDAC2‐mediated proliferation of trophoblast cells requires the miR‐183/FOXA1/IL‐8 signaling pathway

Retracted: HDAC2‐mediated proliferation of trophoblast cells requires the miR‐183/FOXA1/IL‐8 signaling pathway

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods

Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

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