Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

Yoo, Jakyung; Medina‐Franco, José L.

doi:10.5772/27742

Cited by 12 publications

(10 citation statements)

References 85 publications

(105 reference statements)

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“…The growing availability of three-dimensional structures presented in the previous chapter raises the possibility to deploy structure-based drug design (SBDD) techniques, like docking or pharmacophore screenings, in search of novel compounds able to modulate these targets [51,601,602]. Several extensive reviews have been published recently on this topic [19,227,231,361,603].…”

Section: Application Of Computer-aided Drug Design Techniquesmentioning

confidence: 99%

“…Comprehensive reviews providing more detail on inhibitor development and major milestones in targeting DNMTs have been published recently [65,227,357,360,361,413].…”

Section: Dna Methyltransferasesmentioning

confidence: 99%

“…In PMTs the SAM binding pocket entrance is in the opposite position of the hydrophobic and narrow histone (Lys or Arg) binding pocket of the methyltransferase; these two tunnels have a contact area where methylation of histones occurs [73,364]. Several reviews published recently, including one of the current journal issue, describe the mechanism of action of PMTs [41,72,73,191,355,[357][358][359][360][361][362][363]. Because of the importance of PMTs as new biological targets for anticancer therapy, elucidation of their structure is fundamental to undertake drug design campaigns.…”

Section: Histone Methyltranferasesmentioning

confidence: 99%

“…PMTs emerged recently as new important targets for cancer therapy since they were found to be overexpressed or repressed in several types of cancer [73]. PKMTs can mono-, di-or tri-methylate target Lys residues, whereas PRMTs are able to mono-or di-methylate the histone Arg residues [41,72,73,191,355,[357][358][359][360][361][362][363]. PKMTs share a conserved active site in the socalled SET (Su(Var)3-9, Enhancer of zeste, Trithirax) domain.…”

Section: Histone Methyltranferasesmentioning

confidence: 99%

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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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Section: Application Of Computer-aided Drug Design Techniquesmentioning

confidence: 99%

“…Comprehensive reviews providing more detail on inhibitor development and major milestones in targeting DNMTs have been published recently [65,227,357,360,361,413].…”

Section: Dna Methyltransferasesmentioning

confidence: 99%

Section: Histone Methyltranferasesmentioning

confidence: 99%

Section: Histone Methyltranferasesmentioning

confidence: 99%

See 2 more Smart Citations

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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show abstract

“…As part of on-going efforts to conduct virtual screening for novel DNMT inhibitors [19][20][21] and compounds directed to other targets of therapeutic interest [22,23] herein, we report a comprehensive chemoinformatic characterization of a focused library on DNMT inhibitors, two natural products databases including the TCM collection available in ZINC, and other reference databases. The analysis was performed using a comprehensive and complementary set of criteria including physicochemical properties, molecular fingerprints, and scaffolds [13].…”

Section: Introductionmentioning

confidence: 99%

Chemoinformatic Approaches for Inhibitors of DNA Methyltransferases: Comprehensive Characterization of Screening Libraries

Yoo¹,

Luis²

2011

CMB

Self Cite

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Virtual screening of compound databases is a promising approach to identify inhibitors of DNA methyltransferases and other epigenetic targets. An important first step before conducting virtual screening is to characterize the structural diversity and chemical space coverage of the screening collections. Herein, we report a comprehensive chemoinformatic characterization of novel screening libraries, including a focused collection directed to inhibitors of DNA methyltransferases (DNMTs), and two natural product databases. The compound databases were assessed in terms of physicochemical properties, molecular scaffolds, and fingerprints. As part of the scaffold diversity analysis, a recently developed method, based on Shannon Entropy, was used. The overall approach enabled the analysis of property space coverage, degree of overlap between collections, scaffold and structural diversity. Overall, the analysis of the distribution of physicochemical properties indicates that the DNMT focused library and the two natural products collections have molecules with properties similar to approved drugs. Moreover, the natural products databases analyzed in this work have different chemical structures from approved drugs and synthetic databases and therefore are attractive for virtual screening for DNMT inhibitors. The scaffold analysis revealed that the focused library has, overall, the largest scaffold diversity and that the most frequent scaffolds are not identified in the other analyzed collections. Therefore, the focused library is also attractive to perform virtual and experimental screening for novel inhibitors. This study represents a first step towards the virtual screening of novel compound databases to identify inhibitors of DNMTs. Results of this study are general and can be used for the virtual screening of the compound databases against targets directed to other therapeutic applications.

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Molecular Approaches to Explore Natural and Food-Compound Modulators in Cancer Epigenetics and Metabolism

Río

Costa

2014

Foodinformatics

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Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

Cited by 12 publications

References 85 publications

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

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

Chemoinformatic Approaches for Inhibitors of DNA Methyltransferases: Comprehensive Characterization of Screening Libraries

Molecular Approaches to Explore Natural and Food-Compound Modulators in Cancer Epigenetics and Metabolism

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