DNA methyltransferase (DNMT) inhibitors are compounds that interfere with DNA methyltransferase enzymes. These enzymes add methyl groups to DNA, a process called DNA methylation. Inhibitors block this methylation, altering gene expression and modifying cellular processes, especially those implicated in disease.
The Role of DNA Methylation
DNA methylation is a naturally occurring epigenetic process where a methyl group is added to the cytosine base of DNA. This modification does not change the underlying DNA sequence but can significantly influence gene activity. It often turns genes “off.”
This process is fundamental for normal biological functions, including gene regulation, genomic imprinting, and X-chromosome inactivation. DNA methylation helps maintain genomic stability and guides cellular differentiation.
While DNA methylation is a normal and necessary process, abnormal patterns can contribute to disease. For instance, the inappropriate addition of methyl groups can silence tumor suppressor genes. Conversely, too little methylation in certain regions can lead to genomic instability.
How DNMT Inhibitors Function
DNMT inhibitors reduce DNA methylation, leading to a state called hypomethylation. These compounds can bind to the active site of the enzymes, preventing them from attaching methyl groups to DNA.
Some DNMT inhibitors, such as azacitidine and decitabine, are nucleoside analogs that mimic natural DNA building blocks. When incorporated into DNA during cell replication, these analogs can trap DNMT enzymes, forming a stable bond that leads to the enzyme’s degradation.
This inhibition leads to the re-expression of genes previously silenced by excessive methylation. By reducing methylation in specific regions, DNMT inhibitors can restore the normal function of genes that control cell growth or initiate programmed cell death.
Therapeutic Applications
DNMT inhibitors are primarily used to treat certain cancers, especially hematological malignancies. They are clinically approved for conditions like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
In these cancers, tumor suppressor genes are often silenced by aberrant DNA methylation, contributing to uncontrolled cell growth. DNMT inhibitors reverse this hypermethylation, allowing these tumor suppressor genes to become active again and inhibit tumor progression.
Beyond blood cancers, DNMT inhibitors are also being explored for other cancer types, including solid tumors, and in combination with other therapies like chemotherapy and immunotherapy. Research also investigates their potential in autoimmune disorders and neurological conditions, where abnormal methylation patterns are implicated.
Current and Emerging DNMT Inhibitors
Several DNMT inhibitors are approved for clinical use or are under development. Azacitidine and decitabine are two prominent examples that have received FDA approval.
Azacitidine is approved for treating MDS, acute myeloid leukemia, and chronic myelomonocytic leukemia. Decitabine, another nucleoside analog, is also approved for MDS and AML.
Beyond these established drugs, new generations of DNMT inhibitors are being investigated. These include oral formulations and compounds designed for greater specificity or improved stability. Many DNMT inhibitors are under investigation, with some in preclinical stages and others in clinical trials for various cancers.