A work in progress: The clinical development of histone deacetylase inhibitor

Marsoni, Silvia; Damia, Giovanna; Camboni, Gabriella

doi:10.4161/epi.3.3.6253

Cited by 80 publications

(73 citation statements)

References 70 publications

(88 reference statements)

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“…Although subnanomolar HDAC inhibitors are available, they show poor selectivity among the class I, II, and IV HDACs (Marsoni et al 2008), and although potent sirtuin activators and inhibitors have been reported they also show modest selectivity (Sanders et al 2009). HDAC-specific inhibitors are thus actively being pursued, but obtaining them may be particularly challenging because the class I, II, IV, and class III HDACs each share a highly homologous active site and catalytic mechanism (Marsoni et al 2008).…”

Section: Writers and Readers Of Histone Acetylationmentioning

confidence: 99%

Writers and Readers of Histone Acetylation: Structure, Mechanism, and Inhibition

Marmorstein

Zhou

2014

Cold Spring Harbor Perspectives in Biology

476

362

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SUMMARYHistone acetylation marks are written by histone acetyltransferases (HATs) and read by bromodomains (BrDs), and less commonly by other protein modules. These proteins regulate many transcription-mediated biological processes, and their aberrant activities are correlated with several human diseases. Consequently, small molecule HAT and BrD inhibitors with therapeutic potential have been developed. Structural and biochemical studies of HATs and BrDs have revealed that HATs fall into distinct subfamilies containing a structurally related core for cofactor binding, but divergent flanking regions for substratespecific binding, catalysis, and autoregulation. BrDs adopt a conserved left-handed four-helix bundle to recognize acetyllysine; divergent loop residues contribute to substrate-specific acetyllysine recognition.

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Section: Writers and Readers Of Histone Acetylationmentioning

confidence: 99%

Writers and Readers of Histone Acetylation: Structure, Mechanism, and Inhibition

Marmorstein

Zhou

2014

Cold Spring Harbor Perspectives in Biology

476

362

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“…[5,6] In cancerous states, abnormal HDAC activity can lead to aberrant expression of genes regulating cell proliferation, cell cycle, and apoptosis and transcriptional repression of tumor suppressor genes. [3,7] Furthermore, HDACs are known to regulate the acetylation (and thus function) of various non-histone proteins important for cell growth and differentiation, including tumor suppressors. [3,8] Human HDACs are subdivided into 4 classes.…”

Section: Histone Deacetylases: Overview and Inhibition In Cancermentioning

confidence: 99%

Targeting histone deacetylases in T-cell lymphoma

Moskowitz

Horwitz

2016

Leukemia & Lymphoma

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“…This data provided the structural basis for the catalytic mechanism and the inhibition of this family of enzymes, paving the way for the design of new bioactive molecules able to interfere with the deacetylation reaction. Several compounds targeting HDACs entered clinical trials in the last year and have been reviewed elsewhere [98,105,139,141,234,237,[240][241][242][243]. These proteins belong to the open / folding class, with an eight-stranded parallel -sheet sandwiched between -helices.…”

Section: Class I Ii and Iv Deacetylasesmentioning

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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A work in progress: The clinical development of histone deacetylase inhibitor

Cited by 80 publications

References 70 publications

Writers and Readers of Histone Acetylation: Structure, Mechanism, and Inhibition

Writers and Readers of Histone Acetylation: Structure, Mechanism, and Inhibition

Targeting histone deacetylases in T-cell lymphoma

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

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