Lysine demethylases inhibitors

T Suzuki, N Miyata - Journal of medicinal chemistry, 2011 - ACS Publications
T Suzuki, N Miyata
Journal of medicinal chemistry, 2011ACS Publications
Recent studies have revealed that chromatin remodeling, caused by DNA methylation and
histone modifications such as acetylation, methylation, and phosphorylation, plays a pivotal
role in DNA replication/repair and the regulation of epigenetic gene expression. 1À6 Among
the posttranscriptional histone modifications, lysine methylation is one of the most widely
studied, and methylation at various sites, including lysine 26 of histone 1 (H1K26), H3K4,
H3K9, H3K27, H3K36, H3K79, and H4K20, has been shown to lead to transcriptional …
Recent studies have revealed that chromatin remodeling, caused by DNA methylation and histone modifications such as acetylation, methylation, and phosphorylation, plays a pivotal role in DNA replication/repair and the regulation of epigenetic gene expression. 1À6 Among the posttranscriptional histone modifications, lysine methylation is one of the most widely studied, and methylation at various sites, including lysine 26 of histone 1 (H1K26), H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20, has been shown to lead to transcriptional activation or silencing. 7 In general, methylation at H3K4 is associated with actively transcribed gene loci, whereas methylation at H3K9 and H3K27 leads to transcriptional silencing. 8 However, the situation is further complicated by the fact that the ε-amino group of lysine residues can be mono-, di-, or trimethylated, and differential methylation at each lysine methylation site provides functional diversity. For example, dimethylation at H3K4 is associated with both inactive and active genes, whereas trimethylation is exclusive to active genes. 9
In contrast to other histone modifications, such as acetylation and phosphorylation, histone lysine methylation had been regarded as irreversible because of the high thermodynamic stability of the NÀC bond. Indeed, while a number of histone lysine methyltransferases (HKMTs) had been identified by 2003, 7 histone lysine demethylases (KDMs) had not been identified. However, two classes of KDMs have been identified since 2004. One class includes lysine-specific demethylase 1 (LSD1, also known as KDM1A) and LSD2 (also known as KDM1B), which are flavin-dependent amine oxidase domain-containing enzymes. 10, 11 The other class comprises the recently discovered Jumonji domaincontaining protein (JMJD) histone demethylases, 12, 13 which are Fe (II) and α-ketoglutarate-dependent enzymes. The identification of these KDMs established that histone methylation is reversibly regulated by HKMTs and KDMs. As there is increasing evidence that KDMs are associated with various disease states, 14 they have emerged as attractive targets for the development of new therapeutic drugs. To date, several classes of KDM inhibitors have been identified. In this Perspective, we review the reported KDM inhibitors and discuss their potential as therapeutic agents.
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