From design to clinic: Medicinal chemistry and pharmacology of approved epigenetic drugs.

Many diseases, including cancer, are characterized by increased or decreased expression of specific genes. These changes can occur without genome alteration, primarily modulated by the addition or removal of epigenetic markers, which influence chromatin condensation and architecture. Genes in more condensed chromatin regions have lower expression and the opposite also applies. In the last twenty-two years, small molecule inhibitors of enzymes responsible for chromatin deacetylation or methylation have successfully moved from preclinical discovery to clinical therapy. This review explores the ten epigenetic drugs that have attained worldwide regulatory approval for human therapy: the DNA methyltransferase inhibitors azacitidine (2004) and decitabine (2006), the histone deacetylase inhibitors vorinostat (2006), romidepsin (2009), belinostat (2014), panobinostat (2015) tucidinostat (2015) and givinostat (2024), and the histone methyltransferase inhibitors tazemetostat (2020) and valemetostat (2022). The history and strategy of their discovery and development, their biological targets and mechanisms of action and their therapeutic use. In addition, current advancements and efforts, as well as future perspectives in the design and clinical approval of new epigenetic drugs are discussed.