Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Andreoli, Federico; Barbosa, Arménio Jorge Moura; Parenti, Marco; Río, Alberto Del

doi:10.2174/138161213804581918

Cited by 59 publications

(33 citation statements)

References 601 publications

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“…Epigenetic traits are tightly regulated by two major epigenetic modifications: chemical modifications to the cytosine residues of DNA (DNA methylation) and histone proteins associated with DNA (histone modifications) [44], [45]. Studies of epigenetic regulation to potentiate antiviral responses have recently emerged [56].…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Analysis of Antiviral Signature Genes in Porcine Macrophages at Different Activation Statuses

et al. 2014

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Macrophages (MФs) can be polarized to various activation statuses, including classical (M1), alternative (M2), and antiviral states. To study the antiviral activation status of porcine MФs during porcine reproductive and respiratory syndrome virus (PRRSV) infection, we used RNA Sequencing (RNA-Seq) for transcriptomic analysis of differentially expressed genes (DEGs). Sequencing assessment and quality evaluation showed that our RNA-Seq data met the criteria for genome-wide transcriptomic analysis. Comparisons of any two activation statuses revealed more than 20,000 DEGs that were normalized to filter out 153–5,303 significant DEGs [false discovery rate (FDR) ≤0.001, fold change ≥2] in each comparison. The highest 5,303 significant DEGs were found between lipopolysaccharide- (LPS) and interferon (IFN)γ-stimulated M1 cells, whereas only 153 significant DEGs were detected between interleukin (IL)-10-polarized M2 cells and control mock-activated cells. To identify signature genes for antiviral regulation pertaining to each activation status, we identified a set of DEGs that showed significant up-regulation in only one activation state. In addition, pathway analyses defined the top 20–50 significantly regulated pathways at each activation status, and we further analyzed DEGs pertinent to pathways mediated by AMP kinase (AMPK) and epigenetic mechanisms. For the first time in porcine macrophages, our transcriptomic analyses not only compared family-wide differential expression of most known immune genes at different activation statuses, but also revealed transcription evidence of multiple gene families. These findings show that using RNA-Seq transcriptomic analyses in virus-infected and status-synchronized macrophages effectively profiled signature genes and gene response pathways for antiviral regulation, which may provide a framework for optimizing antiviral immunity and immune homeostasis.

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Section: Resultsmentioning

confidence: 99%

Genome-Wide Analysis of Antiviral Signature Genes in Porcine Macrophages at Different Activation Statuses

et al. 2014

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“…PRC2 inactivation also triggers an epigenetic switch from H3K37Me3 to H3K27Ac. Histone acetylation/deacetylation status is a crucial epigenetic regulation of gene expression and addition of acetyl groups to histone lysine residues by histone acetyl transferase turns the chromatin to an active transcriptional state [35]. The bromodomain and extra-terminal (BET) family (BRD2, BRD3, BRD4 and BRDT) function as readers of the acetylated chromatin.…”

Section: Discussionmentioning

confidence: 99%

“…The bromodomain and extra-terminal (BET) family (BRD2, BRD3, BRD4 and BRDT) function as readers of the acetylated chromatin. Deregulation of these proteins is found in several diseases including cancer [35]. Therefore, they are attractive potential therapeutic targets for new anticancer drug development.…”

Section: Discussionmentioning

confidence: 99%

Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

et al. 2016

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Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive “active-site” mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.

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“…Drug discovery approaches targeting key epigenetic enzymes with small‐molecule inhibitors have resulted in pre‐clinical and clinical agents . Histone deacetylases (HDAC) and lysine specific demethylase 1 (LSD1) are two of the major epigenetic targets in anticancer drug discovery.…”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

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Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

Cited by 59 publications

References 601 publications

Genome-Wide Analysis of Antiviral Signature Genes in Porcine Macrophages at Different Activation Statuses

Genome-Wide Analysis of Antiviral Signature Genes in Porcine Macrophages at Different Activation Statuses

Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

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