Inhibitors of Jumonji-C domain-containing histone demethylases

Abstract

[Inicio] Histone methylation represents an epigenetic modification that plays important roles not only for the transcriptional regulation but also for the preservation of genomic stability in eukaryotes. The methylation status of specific lysines is kept in balance by the competitive roles of two enzyme families, that is, the histone methyltransferases (HMTs) [1,2] and the histone demethylases (KDMs) [3-7]. A variety of diseases, including inflammation, leukemia, and breast and prostate cancers, are linked to alterations from its normal status of this epigenetic modification [8,9]. Nine groups of human Nε-methyl-lysine demethylases (KDM1-9) have been identified that catalyze the demethylation of N-methyl-lysine residues in histones through oxidative mechanisms acting on different Nε-methylation states and specific protein sequences [3]. KDMs are grouped into two families: the flavin-dependent lysine-specific demethylases (LSDs/KDM1s) and the 2-oxoglutarate (2OG)-, ferrous iron-, and oxygen-dependent demethylases [Jumonji-C (JmjC) KDMs], the latter being the largest family of KDMs. More than 100 members of the JmJC domaincontaining proteins have been reported, including KDMs [10]. [...]