Recent Prospectives of Anticancer Histone Deacetylase Inhibitors

Abbass, Shymaa A.; Hassan, Heba A.; Mohamed, Mamdouh F. A.; Moustafa, Gamal A. I.; Abuo‐Rahma, Gamal El‐Din A.

doi:10.21608/jabps.2019.14468.1051

Cited by 7 publications

(11 citation statements)

References 133 publications

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“…These inhibitors are divided into five subgroups based on their chemical structure: short-chain fatty acids that include hydroxamic acids, benzamides, cyclic peptides, and sirtuin inhibitors [ 19 , 176 , 191 ]. The functions of immune system cells with excessive accumulation of acetylated histones may be altered and it is therefore of the utmost importance to carefully select HDACis for the treatment of diseases such as cancer [ 175 ].…”

Section: Inhibitors Of Hdacsmentioning

confidence: 99%

“…The presence of acetylated lysine in the histone tail results in a relaxed chromatin state, allowing the activation of gene transcription in that region. On the other hand, the deacetylation of lysine residues is associated with condensed chromatin, which impedes the transcription of genes present in that chromatin region [ 19 , 20 ]. The acetylation and deacetylation of lysine residues is controlled by two enzymes with opposite activities involved in gene regulation [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Verza

Das

Fachin

et al. 2020

Cancers

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Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.

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Section: Inhibitors Of Hdacsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Verza

Das

Fachin

et al. 2020

Cancers

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“…RedFK, Belinostat (PXD101), Pracinostat, Panobinostat (LBH-589) and Chidamide (CS055) [15][16][17][18][19] .…”

Section: Fig 2: Structure Of the Approved Anticancer Hdacismentioning

confidence: 99%

“…1 in histones and non-histone proteins 14 . HATs transfer the acetyl group via acetyl-CoA, and HDACs/SIRTs deacetylate ε-N-acetylated lysine residues using Zn 2+ (HDACs) or NAD + (SIRTs) as cofactors 15 .…”

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confidence: 99%

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2020

IJPSR

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The outburst of new coronavirus (COVID-19) infections, firstly appeared in Wuhan in 2019, has massively expanded to the whole world. At the end of March 2020, the rapid spread of the infection happened in about 206 countries around the globe. At the moment, the statistics of WHO on coronavirus pandemic revealed total infected cases of 21,770,000 and more than 77,000 deaths all over the world, with no proven antiviral agent available yet to control COVID-19 infection. The world is currently in desperate need of finding potent therapeutic agents. Histone deacetylases (HDACs) represent one of the most promising viral targets. Importantly, HDACs are critical factors involved in the control of viral replication. The molecular mechanisms associated with underlying the role of HDACs in viral latency, viral reactivation, and carcinogenesis are progressively disclosed. Till now, six HDACIs anticancer drugs have been approved by the FDA. Herein, in the in-silico structurebased drug design approach was utilized to identify novel structural characteristics for the potential repurposed activity of HDACIs as antivirals for COVID-19. In this respect, 12 HDACIs were carefully screened to probe their possible anti-viral activity against SARS-CoV main proteaseM pro (PDB: 6LU7). Most of the screened HDACIs are strongly bind into the active binding site of crystallographic structure of M pro (PDB: 6LU7) with comparable docking energy and hydrogen bond formation. These findings demonstrate that HDACIs, especially Romidepsin and its active form (RedFK), hold promise as COVID-19 protease inhibitors. Moreover, calculations of physicochemical parameters and drug-likeness properties of the screened compounds implied an acceptable ADMET for all tested compounds. INTRODUCTION: In the last few weeks of 2019, an unprecedented global outbreak of novel coronavirus (COVID-19) (2019-nCoV; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, detected firstly in Wuhan, China in patients having severe pneumonia 1-5 .

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“…Up to date, there are six HDAC inhibitors (Figure 1) have been FDAapproveed; Vorinostat (SAHA) 1 [12], Romidepsin (FK228) 2a and its active metabolite RedFK 2b [13], Belinostat (PXD101) 3 [14], Pracinostat 4 [15], Panobinostat (LBH-589) 5 [16] are approved by the FDA while (Chidamide) 6 is approved by the Chinese FDA for the therapy of hematological malignancies (CS055) [17,18]. The X-ray arrangement disclosed that HDAC inhibitors consist of the following pharmacophores, namely; a cap group (CAP), the zinc-binding group (ZBG); and a spacer (hydrophobic linker) and a polar connection unit (CU, evidently unessential for HDAC8 selective inhibitors) (Figure 1) [19]. HDAC inhibitors have shown encouraging findings against hematological malignancies, but varying on the cancer type and genetic factors, the response to HDAC inhibitors may be based on a certain biological response [20].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

2021

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Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. Therefore, in this work, based on introducing 3,4,5-trimethoxy phenyl group as a part of the CAP moiety, in addition to incorporating 4–6 aliphatic carbons linker and using COOH or hydroxamic acid as ZBG, 12 novel EGFR/HDAC hybrid inhibitors 2a–c, 3a–c, 4a–c and 5a–c were designed, constructed, and evaluated for their anticancer activities against 4 cancer cell lines (HepG2, MCF-7, HCT116 and A549). Among all, hybrids with hydroxamic acid 4a–c and 5a, exhibited the highest inhibition against all cancer cell lines with IC50 ranging from 0.536 to 4.892 μM compared to Vorinostat (SAHA) with IC50 ranging from 2.43 to 3.63 μM and Gefitinib with IC50 ranging from 1.439 to 3.366 μM. Mechanistically, the most potent hybrids 4a–c and 5a were further tested for their EGFR and HDACs inhibitory activities. The findings disclosed that hybrid 4b displayed IC50 = 0.063 µM on the target EGFR enzyme which is slightly less potent than the standard Staurosporine (IC50 = 0.044 µM). Furthermore, hybrid 4b showed less HDAC inhibitory activity IC50 against HDAC1 (0.148), 2 (0.168), 4 (5.852), 6 (0.06) and 8 (2.257) than SAHA. In addition, the investigation of apoptotic action of the most potent hybrid 4b showed a significant increase in Bax level up to 3.75-folds, with down-regulation in Bcl2 to 0.42-fold, compared to the control. Furthermore, hybrid 4b displayed an increase in the levels of Caspases 3 and 8 by 5.1 and 3.15 folds, respectively. Additionally, the cell cycle analysis of hybrid 4b revealed that it showed programmed cell death and cell cycle arrest at G1/S phase. Moreover, all these outcomes together with the molecular docking study recommended the rationalized target hybrids 4a–c and 5a, particularly 4b, may be considered to be promising lead candidates for discovery of novel anticancer agents via dual inhibition of both EGFR/HDAC enzymes.

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Recent Prospectives of Anticancer Histone Deacetylase Inhibitors

Cited by 7 publications

References 133 publications

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

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Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

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