Pharmacoepigenetics: Novel Mechanistic Insights in Drug Discovery and Development Targeting Chromatin-Modifying Enzymes

Abstract Pharmacoepigenetics is the study of the epigenetic basis for individual variations in drug response. There is growing evidence that pharmacoepigenetics has the potential to become an important element of personalized medicine. New developments in epigenetics can be applied in the areas of drug pharmacokinetics and pharmacodynamics. Epigenetic modifications involved in the development and progression of cancer can be grouped into DNA methylation, microRNAs, covalent histone modifications, and nucleosome remodeling. These mechanisms are discrete, but interact closely to regulate gene expression. Epigenetic modifications involved in the regulation of gene expression are balanced by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). The acetylation of histones provides a more open chromatin structure that correlates with gene activation, while histone deacetylation mediates transcriptional repression. Histone deacetylase inhibitors (HDACi) are a new class of small-molecule chemotherapeutics that target chromatin remodeling through the regulation of histone and nonhistone proteins. Urea-based derivatives also play an important role in generating anticancer activity, and various urea-containing compounds exhibit admirable anticancer activity. (E)-1,3-dicyclohexyl-1-(3-(3,4-dimethoxyphenyl)acryloyl)urea , which acts as an HDACi directed against HDAC enzymes, has become an important therapeutic tool in oncology. Consequently, scientific efforts have fortified the quest for newer and novel HDACi, which should result in the design of structurally innovative HDACi.