Histone Deacetylase Inhibitors

Jones, Philip

doi:10.1002/9783527627073.ch9

Cited by 6 publications

(8 citation statements)

References 100 publications

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Section: Main Textmentioning

confidence: 99%

“…HDAC inhibitors [ 23 ] emulate the native acetylated lysine using a Zn 2+ -chelating “head group” attached via a connector of variable length and functionality to a cap region. The Zn 2+ -chelating “head groups” reported in HDACis includes virtually all functionalities known to bind transition metal ions (hydroxamic acids, thiols, mercaptoamides, trifluoromethylketones…), which most likely compete with the natural substrate after binding site occupancy [ 23 ]. For general inhibition by hydroxamic acids, a spontaneous proton transfer to an active site histidine upon binding of the inhibitor to the zinc was supported by recent computations; accordingly, for thiol-containing inhibitors (or precursors such as disufides or thioesters), the thiolate appears to be the active species [ 22 ].…”

Section: Main Textmentioning

confidence: 99%

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Epigenetic polypharmacology: from combination therapy to multitargeted drugs

2016

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The modern drug discovery process has largely focused its attention in the so-called magic bullets, single chemical entities that exhibit high selectivity and potency for a particular target. This approach was based on the assumption that the deregulation of a protein was causally linked to a disease state, and the pharmacological intervention through inhibition of the deregulated target was able to restore normal cell function. However, the use of cocktails or multicomponent drugs to address several targets simultaneously is also popular to treat multifactorial diseases such as cancer and neurological disorders. We review the state of the art with such combinations that have an epigenetic target as one of their mechanisms of action. Epigenetic drug discovery is a rapidly advancing field, and drugs targeting epigenetic enzymes are in the clinic for the treatment of hematological cancers. Approved and experimental epigenetic drugs are undergoing clinical trials in combination with other therapeutic agents via fused or linked pharmacophores in order to benefit from synergistic effects of polypharmacology. In addition, ligands are being discovered which, as single chemical entities, are able to modulate multiple epigenetic targets simultaneously (multitarget epigenetic drugs). These multiple ligands should in principle have a lower risk of drug-drug interactions and drug resistance compared to cocktails or multicomponent drugs. This new generation may rival the so-called magic bullets in the treatment of diseases that arise as a consequence of the deregulation of multiple signaling pathways provided the challenge of optimization of the activities shown by the pharmacophores with the different targets is addressed.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

2016

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“…Vorinostat (Zolinza ® ) was the fi rst HDACi to be approved by the FDA for the treatment of cutaneous T-cell lymphoma in 2006. It has been shown that vorinostat is able to induce differentiation, cell growth arrest and apoptosis in numerous cancer cell lines at low micromolar concentrations and inhibits tumour growth with little toxicity in a wide range of animal models (Jones 2009 ). Panobinostat, an orally available HDACi, shows antiproliferative and cytotoxic activity in a variety of cancer cell lines and induces hyperacetylation of histone H3 and H4 (Atadja 2009 ).…”

Section: Hdac Inhibitors (Hdaci)mentioning

confidence: 98%

Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy

Keller¹,

Jung²

2013

Epigenetic Therapy of Cancer

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Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histonemodifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects.

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“…Vorinostat induces cellular differentiation, e.g., of erythroleukemia cells, causes increased levels of p21 and G1 cell cycle arrest. The compound inhibits cell growth in a variety of different tumor cell lines and animal models with little toxicity (Jones 2009 ).…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Wagner¹,

Hackanson²,

Lübbert³

et al. 2010

Clin Epigenet

357

302

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Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects.

show abstract

Histone Deacetylase Inhibitors

Cited by 6 publications

References 100 publications

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

Epigenetic polypharmacology: from combination therapy to multitargeted drugs

Histone Deacetylase (HDAC) Inhibitors in Recent Clinical Trials for Cancer Therapy

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

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