DNMTinhibitors

DNMT inhibitors are a class of drugs that target DNA methyltransferases, enzymes that add methyl groups to cytosine bases in genomic DNA, typically at CpG sites. Inhibition of these enzymes leads to DNA hypomethylation and can result in reactivation of silenced genes, including tumor suppressors, contributing to differentiation and apoptosis of malignant cells. The class includes two main categories: nucleoside analogs and non-nucleoside inhibitors. The nucleoside analogs, known as hypomethylating agents, include azacitidine and decitabine. These cytidine analogs are phosphorylated and incorporated into RNA and DNA; when DNMT enzymes attempt to methylate these modified nucleotides, they form covalent adducts and become depleted, resulting in progressive DNA hypomethylation during cell replication. These agents are approved for myelodysplastic syndromes and are used in certain subtypes of acute myeloid leukemia; azacitidine also has broader applications in other myeloid disorders. In addition, oral formulations of azacitidine have been developed for maintenance therapy and other indications.

Administration and pharmacology vary by compound. Azacitidine is given subcutaneously or intravenously, while decitabine is typically intravenous; dosing schedules are cycle-based and depend on disease context. Guadecitabine (SGI-110) is a prodrug of decitabine designed to provide longer exposure. Non-nucleoside DNMT inhibitors exist and are the subject of ongoing research, aiming to inhibit DNMT enzymes without incorporation into DNA.

Safety considerations include hematologic toxicity, such as cytopenias, fatigue, infections, and gastrointestinal symptoms. Responses may take several cycles, and combinations with other therapies are actively explored.