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Dual Inhibitors Against Topoisomerases and Histone Deacetylases.

Seo YH - J Cancer Prev (2015)

Bottom Line: Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins.Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use.This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, Korea.

ABSTRACT
Topoisomerases and histone deacetylases (HDACs) are considered as important therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs. In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

No MeSH data available.


Related in: MedlinePlus

Post-translational modification of the lysine ε-amino group and histone deacetylase (HDAC) inhibitors. (A) Acetylation and de-acetylation of the lysine ε-amino group are mediated by histone acetyltransferases (HATs) and HDACs, respectively. (B) Pharmacophore model of HDAC inhibitors and their representative structures. SAHA, suberoylanilide hydroxamic acid; ZBG, zinc binding group.
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f3-jcp-20-85: Post-translational modification of the lysine ε-amino group and histone deacetylase (HDAC) inhibitors. (A) Acetylation and de-acetylation of the lysine ε-amino group are mediated by histone acetyltransferases (HATs) and HDACs, respectively. (B) Pharmacophore model of HDAC inhibitors and their representative structures. SAHA, suberoylanilide hydroxamic acid; ZBG, zinc binding group.

Mentions: HDACs are a class of epigenetic enzymes which remove acetyl groups from N-acetyl lysine amino acids on histones, allowing histones to wrap DNA tightly (Fig. 3A).40–43 There are eleven zinc-dependent HDAC isoforms which can be classified into three classes depending on their sequence homology. Class I comprises HDAC 1, 2, 3, and 8, localized to the nucleus and class II a/b consists of HDAC 4, 5, 6, 7, 9, and 10 found in the nucleus and cytoplasm. HDAC11 is a sole member of class IV and shares sequence similarity to classes I and II. Additionally, zinc-independent seven isoforms, Sirt1-7 are referred to as class III, which utilize NAD+ as a cofactor as opposed to zinc. HDACs along with histone acetyltransferases (HATs) are important classes of enzymes which regulate a dynamic post-translational modification of the lysine by acetylating and de-acetylating ε-amino group of the residue on proteins including histones. HDACs function was originally discovered to remove acetyl groups from histone proteins, leading to a condensed structure and transcriptional suppression, while histone acetylation by HATs results in a relaxed chromatin structure that is associated with the transcriptional upregulation. Interestingly, recent evidence has illustrated that HDACs are involved in the deacetylation of important non-histone regulatory proteins such as p53, E2F, α-tubulin, and Hsp90.12–16 Collectively, inhibition of HDACs enzymatic activity can induce growth arrest and apoptosis in tumor cells. Therefore, HDACs have emerged as novel therapeutic targets for cancer treatment, and thereby two broad spectrum HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and FK228 have been approved for the treatment of cutaneous T-cell lymphoma.44–46


Dual Inhibitors Against Topoisomerases and Histone Deacetylases.

Seo YH - J Cancer Prev (2015)

Post-translational modification of the lysine ε-amino group and histone deacetylase (HDAC) inhibitors. (A) Acetylation and de-acetylation of the lysine ε-amino group are mediated by histone acetyltransferases (HATs) and HDACs, respectively. (B) Pharmacophore model of HDAC inhibitors and their representative structures. SAHA, suberoylanilide hydroxamic acid; ZBG, zinc binding group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492363&req=5

f3-jcp-20-85: Post-translational modification of the lysine ε-amino group and histone deacetylase (HDAC) inhibitors. (A) Acetylation and de-acetylation of the lysine ε-amino group are mediated by histone acetyltransferases (HATs) and HDACs, respectively. (B) Pharmacophore model of HDAC inhibitors and their representative structures. SAHA, suberoylanilide hydroxamic acid; ZBG, zinc binding group.
Mentions: HDACs are a class of epigenetic enzymes which remove acetyl groups from N-acetyl lysine amino acids on histones, allowing histones to wrap DNA tightly (Fig. 3A).40–43 There are eleven zinc-dependent HDAC isoforms which can be classified into three classes depending on their sequence homology. Class I comprises HDAC 1, 2, 3, and 8, localized to the nucleus and class II a/b consists of HDAC 4, 5, 6, 7, 9, and 10 found in the nucleus and cytoplasm. HDAC11 is a sole member of class IV and shares sequence similarity to classes I and II. Additionally, zinc-independent seven isoforms, Sirt1-7 are referred to as class III, which utilize NAD+ as a cofactor as opposed to zinc. HDACs along with histone acetyltransferases (HATs) are important classes of enzymes which regulate a dynamic post-translational modification of the lysine by acetylating and de-acetylating ε-amino group of the residue on proteins including histones. HDACs function was originally discovered to remove acetyl groups from histone proteins, leading to a condensed structure and transcriptional suppression, while histone acetylation by HATs results in a relaxed chromatin structure that is associated with the transcriptional upregulation. Interestingly, recent evidence has illustrated that HDACs are involved in the deacetylation of important non-histone regulatory proteins such as p53, E2F, α-tubulin, and Hsp90.12–16 Collectively, inhibition of HDACs enzymatic activity can induce growth arrest and apoptosis in tumor cells. Therefore, HDACs have emerged as novel therapeutic targets for cancer treatment, and thereby two broad spectrum HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and FK228 have been approved for the treatment of cutaneous T-cell lymphoma.44–46

Bottom Line: Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins.Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use.This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, Korea.

ABSTRACT
Topoisomerases and histone deacetylases (HDACs) are considered as important therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs. In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.

No MeSH data available.


Related in: MedlinePlus