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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

Pharmacophoric features of dual inhibitors against histone deacetylases and topoisomerases and their chemical structures. ZBG, zinc binding group.
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f4-jcp-20-85: Pharmacophoric features of dual inhibitors against histone deacetylases and topoisomerases and their chemical structures. ZBG, zinc binding group.

Mentions: In 2012, Guerrant et al.54 for the first time introduced dual inhibitors targeting HDACs and topoisomerase II. In this study, they covalently combined HDAC inhibitor, SAHA with topoisomerase II inhibitor, daunorubicin to furnish a novel dual acting agent, 1 in Figure 4.54 Compound 1 potently inhibited the proliferation of cancer cells, including DU-145, SK-MES-1, and MCF-7. Interestingly, compound 1 displayed substantially high anti-proliferative activity (IC50 = 0.13 μM) against DU-145, prostate carcinoma cell line. As expected, the study of molecular mechanism illustrated that compound 1 presented both HDAC and topoisomerase II inhibition signatures under cell-free condition and in vitro cell cultures.


Dual Inhibitors Against Topoisomerases and Histone Deacetylases.

Seo YH - J Cancer Prev (2015)

Pharmacophoric features of dual inhibitors against histone deacetylases and topoisomerases and their chemical structures. ZBG, zinc binding group.
© Copyright Policy
Related In: Results  -  Collection

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

f4-jcp-20-85: Pharmacophoric features of dual inhibitors against histone deacetylases and topoisomerases and their chemical structures. ZBG, zinc binding group.
Mentions: In 2012, Guerrant et al.54 for the first time introduced dual inhibitors targeting HDACs and topoisomerase II. In this study, they covalently combined HDAC inhibitor, SAHA with topoisomerase II inhibitor, daunorubicin to furnish a novel dual acting agent, 1 in Figure 4.54 Compound 1 potently inhibited the proliferation of cancer cells, including DU-145, SK-MES-1, and MCF-7. Interestingly, compound 1 displayed substantially high anti-proliferative activity (IC50 = 0.13 μM) against DU-145, prostate carcinoma cell line. As expected, the study of molecular mechanism illustrated that compound 1 presented both HDAC and topoisomerase II inhibition signatures under cell-free condition and in vitro cell cultures.

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