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Histone deacetylase inhibitors: from target to clinical trials
William K Kelly1, Owen A O'Connor, Paul A Marks
1Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Abstract:
Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in chromatin proteins, for example, histones. The structure of chromatin may be altered by post-translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses.
Insights
Histone deacetylase (HDAC) inhibitors show promise in cancer treatment by arresting cancer cell growth. Hydroxamic acid-based HDAC inhibitors are particularly effective and well-tolerated in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Cancer cells exhibit uncontrolled proliferation but can be induced to arrest growth.
- DNA is packaged into chromatin by histones, and gene expression is regulated by histone post-translational modifications like acetylation.
- Histone deacetylases (HDACs) and histone acetyltransferases control histone acetylation status.
Purpose of the Study:
- To review compounds that inhibit histone deacetylase (HDAC) activity.
- To highlight the role of HDAC inhibitors in cancer therapy.
Main Methods:
- Review of literature on HDAC inhibitors.
- Analysis of in vitro and in vivo studies of HDAC inhibitor efficacy.
- Focus on hydroxamic acid-based HDAC inhibitors.
Main Results:
- HDAC inhibitors induce cancer cell growth arrest, differentiation, and/or apoptosis.
- Several HDAC inhibitors are in clinical trials for cancer treatment.
- Hydroxamic acid-based HDAC inhibitors demonstrate efficacy in cancers with good tolerability.
Conclusions:
- HDAC inhibitors represent a promising class of anticancer agents.
- Targeting histone acetylation through HDAC inhibition offers a viable therapeutic strategy.
- Hydroxamic acid derivatives are leading candidates for further clinical development.