Epigenetic Multiple Ligands: Mixed Histone/Protein Methyltransferase, Acetyltransferase, and Class III Deacetylase (Sirtuin) Inhibitors

Mai, Antonello; Cheng, Donghang; Bedford, Mark T.; Nebbioso, Angela; Perrone, Andrea; Brosch, Gerald; Sbardella, Gianluca; Bellis, Floriana De; Miceli, Marco; Altucci, Lucia

doi:10.1021/jm701595q

Cited by 133 publications

(99 citation statements)

References 89 publications

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“…Consistent with structural diversity, the inhibitors exert biological functions through different mechanisms, such as SIRT1 protein precipitation for sirtinol, competing with the histone peptide substrate but not NAD + for cambinol (12), and mimicking the effect of nicotinamide for tenovins (19). Importantly, a number of chemically synthesized epigenetic multiple ligands have been found to simultaneously inhibit nonhistone and histone methyltransferases, SIRT1 and SIRT2, and induce dramatic differentiation and apoptosis in cancer cells (20).…”

Section: Small Molecule Sirt1 Inhibitors As Anticancer Agentsmentioning

confidence: 90%

The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer

2009

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Gene expression and deacetylase activity of the class III histone deacetylase SIRT1 are up-regulated in cancer cells due to oncogene overexpression or loss of function of tumor suppressor genes. SIRT1 induces histone deacetylation and methylation, promoter CpG island methylation, transcriptional repression, and deacetylation of tumor suppressor proteins. SIRT1 may play a critical role in tumor initiation, progression, and drug resistance by blocking senescence and apoptosis, and promoting cell growth and angiogenesis. SIRT1 inhibitors have shown promising anticancer effects in animal models of cancer. Further screening for more potent SIRT1 inhibitors may lead to compounds suitable for clinical trials in patients.

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Section: Small Molecule Sirt1 Inhibitors As Anticancer Agentsmentioning

confidence: 90%

The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer

2009

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“…Several review articles recently described rationales, targets, new drugs, approaches, novel compounds and methodologies [12,17,18,20,[22][23][24][25][35][36][37][38][39][40][41]65,[226][227][228][229]. A large amount of these insightful articles have been dedicated to well established drug targets such as the histone deacetylases (HDACs) and DNA methyltransferases, and to the status of the development of small-molecule compounds [25,31,45,55,230,231].…”

Section: Structural Data Of Epigenetic Targetsmentioning

confidence: 99%

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

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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“…Epigenetic transcriptional repression of tumor suppressor genes, cell cycle and DNA repair, and activation of invasion-and metastasis-regulating genes has been demonstrated in a wide variety of tumors. Recently, the effects of DNA methyltransferase inhibitors (DNMTi) and/or histone deacetylase inhibitors (HDACi) in advanced cancers have been investigated in clinical trials (6)(7)(8); at least 15 HDACi are currently under clinical investigation either alone or in combination with other therapeutic modalities for the treatment of hematological and solid malignancies (9).…”

Section: Introductionmentioning

confidence: 99%

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

Nebbioso

Carafa

Conte

et al. 2017

Clinical Cancer Research

Self Cite

122

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Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.

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Epigenetic Multiple Ligands: Mixed Histone/Protein Methyltransferase, Acetyltransferase, and Class III Deacetylase (Sirtuin) Inhibitors

Cited by 133 publications

References 89 publications

The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer

The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer

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

c-Myc Modulation and Acetylation Is a Key HDAC Inhibitor Target in Cancer

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