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Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy
Ludovica Morera1, Michael Lübbert2, Manfred Jung3
1Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
Abstract:
The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1.
Insights
Epigenetics, reversible gene expression changes, plays a key role in cancer. Targeting enzymes like DOT1L, EZH2, and LSD1 offers new anticancer drug possibilities in clinical trials.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Epigenetics involves heritable gene expression changes without altering DNA sequence.
- Dysregulated epigenetic processes are crucial in cancer development and progression.
- Epigenetic modifications are reversible, making them targets for drug development.
Purpose of the Study:
- To review enzymes involved in reversible histone methylation.
- To highlight promising targets for anticancer drugs.
- To discuss enzymes and inhibitors in early clinical trials for cancer therapy.
Main Methods:
- Literature review of epigenetic enzymes and their inhibitors.
- Focus on histone methyltransferases (DOT1L, EZH2) and demethylase (LSD1).
- Analysis of enzymes that have reached initial clinical trial stages.
Main Results:
- Histone methylation enzymes DOT1L and EZH2, and demethylase LSD1 are key epigenetic regulators in cancer.
- Inhibitors for these enzymes are under investigation in early-phase clinical trials.
- These enzymes represent promising therapeutic targets for novel anticancer drugs.
Conclusions:
- Epigenetic modifications, particularly histone methylation, are critical in cancer.
- Enzymes like DOT1L, EZH2, and LSD1 are viable targets for pharmacological intervention.
- Targeting these epigenetic regulators offers a promising avenue for new cancer therapies.
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