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Updated: Oct 28, 2025
Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
Next generation epigenetic modulators to target myeloid neoplasms
Daniel Sasca1, Borhane Guezguez1,2,3, Michael W M Kühn1
1Department of Hematology, Oncology, and Pulmonary Medicine, University Medical Center, Johannes Gutenberg-University Mainz, Mainz.
Purpose Of Review:
Comprehensive sequencing studies aimed at determining the genetic landscape of myeloid neoplasms have identified epigenetic regulators to be among the most commonly mutated genes. Detailed studies have also revealed a number of epigenetic vulnerabilities. The purpose of this review is to outline these vulnerabilities and to discuss the new generation of drugs that exploit them.
Recent Findings:
In addition to deoxyribonucleic acid-methylation, novel epigenetic dependencies have recently been discovered in various myeloid neoplasms and many of them can be targeted pharmacologically. These include not only chromatin writers, readers, and erasers but also chromatin movers that shift nucleosomes to allow access for transcription. Inhibitors of protein-protein interactions represent a novel promising class of drugs that allow disassembly of oncogenic multiprotein complexes.
Summary:
An improved understanding of disease-specific epigenetic vulnerabilities has led to the development of second-generation mechanism-based epigenetic drugs against myeloid neoplasms. Many of these drugs have been introduced into clinical trials and synergistic drug combination regimens have been shown to enhance efficacy and potentially prevent drug resistance.
Insights
New epigenetic drugs target vulnerabilities in myeloid neoplasms. These advanced therapies, including novel drug combinations, show promise in clinical trials for enhanced efficacy and overcoming resistance.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Comprehensive sequencing reveals epigenetic regulators are frequently mutated in myeloid neoplasms.
- Epigenetic vulnerabilities are increasingly recognized as key drivers in these cancers.
- Understanding these vulnerabilities is crucial for developing targeted therapies.
Purpose of the Study:
- To review identified epigenetic vulnerabilities in myeloid neoplasms.
- To discuss novel pharmacological agents targeting these vulnerabilities.
- To highlight the development of next-generation epigenetic drugs.
Main Methods:
- Review of recent comprehensive sequencing and genetic landscape studies.
- Analysis of pharmacologically targetable epigenetic dependencies.
- Examination of emerging drug classes, including protein-protein interaction inhibitors.
Main Results:
- Novel epigenetic dependencies beyond DNA methylation have been identified.
- Targetable mechanisms include chromatin writers, readers, erasers, and movers.
- Inhibitors of protein-protein interactions offer a new therapeutic avenue.
Conclusions:
- Second-generation epigenetic drugs are being developed based on disease-specific vulnerabilities.
- Many new epigenetic drugs are in clinical trials for myeloid neoplasms.
- Synergistic drug combinations enhance efficacy and may prevent resistance.
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