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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

Representative structures of topoisomerase I/II inhibitors. DACA, [2-dimethylamino]ethyl]acridine-4-carboxamide.
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f2-jcp-20-85: Representative structures of topoisomerase I/II inhibitors. DACA, [2-dimethylamino]ethyl]acridine-4-carboxamide.

Mentions: Camptothecin (CPT) was first isolated from the Chinese tree Camptotheca acuminate (Fig. 2).21–23 In 1966, drug screening by National Cancer Institute discovered that CPT displayed a marked anticancer activity.23 However, its clinical development was discontinued in the early 1970s, due to the appearance of unacceptable side effects. In 1985 Hsiang et al.24 identified DNA topoisomerase I as the molecular target of CPT that initiated the development of CPT derivatives to obtain clinically applicable anticancer drugs. The extensive studies and efforts introduced a water-soluble CPT derivative, irinotecan (CPT-11), which was approved for clinical use in 1996, more than thirty years after the first isolation of the natural alkaloid CPT.25,26 The main clinical use of irinotecan is for the treatment of colorectal cancer for both first and second line therapy, and irinotecan has also shown clinical activity against lung, gastric, cervical and ovarian cancers, malignant lymphoma and other malignancies.25,27–29


Dual Inhibitors Against Topoisomerases and Histone Deacetylases.

Seo YH - J Cancer Prev (2015)

Representative structures of topoisomerase I/II inhibitors. DACA, [2-dimethylamino]ethyl]acridine-4-carboxamide.
© Copyright Policy
Related In: Results  -  Collection

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

f2-jcp-20-85: Representative structures of topoisomerase I/II inhibitors. DACA, [2-dimethylamino]ethyl]acridine-4-carboxamide.
Mentions: Camptothecin (CPT) was first isolated from the Chinese tree Camptotheca acuminate (Fig. 2).21–23 In 1966, drug screening by National Cancer Institute discovered that CPT displayed a marked anticancer activity.23 However, its clinical development was discontinued in the early 1970s, due to the appearance of unacceptable side effects. In 1985 Hsiang et al.24 identified DNA topoisomerase I as the molecular target of CPT that initiated the development of CPT derivatives to obtain clinically applicable anticancer drugs. The extensive studies and efforts introduced a water-soluble CPT derivative, irinotecan (CPT-11), which was approved for clinical use in 1996, more than thirty years after the first isolation of the natural alkaloid CPT.25,26 The main clinical use of irinotecan is for the treatment of colorectal cancer for both first and second line therapy, and irinotecan has also shown clinical activity against lung, gastric, cervical and ovarian cancers, malignant lymphoma and other malignancies.25,27–29

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