Histone methyltransferases, inhibition

Efforts to identify specific inhibitors of histone methyltransferases are in their early stages, and only two specific KMT inhibitors have been identified. The fungal mycotoxin chaetocin (9, Figure 2) inhibits the KMT Su(var)3-9 from Drosophila with an IC50 of 0.8 iM and produces a... 

Gore, S.D. et al. (2006) Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Research, 66, 6361-6369. 

Relationships between histone methylation and DNA methylation and histone acetyation and DNA methylation have been reported [191,314,315], A similar relationship may exist between poly(ADP ribosylated) HI and DNA methylation. Inhibition of poly(ADP-ribose) polymerase with 3-aminobenzamide increases the susceptibility of L929 mouse fibroblast nuclei to be methylated by endogenous DNA methyltransferases [316,317], Further, there is evidence that poly(ADP ribosylation) protects CpG islands located at the 5 end of housekeeping genes from methylation [318], Future studies will likely reveal an interesting dynamic relationship between histone methylation, histone acetylation, and histone poly(ADP-ribosylation). 

Pseudoceratina purpurea inhibition of both histone deacetylase and DNA methyltransferase. The Journal of Organic Chemistry, 68, 3866-3873. 

STAT4 is responsible for IL-12-mediated functions and for the development of THi cells that secrete IFN-y from naive CD4+ T cells. After IL-12 induces its receptors, STAT4 binds to IL-18yl promoter, which results in an increase in acetylated histones H3 and H4 transiently. The transient hyperacetylation induced by STAT4 inhibits DNA methyltransferase recruitment and the consequent suppression of the IL-18yl locus. 

Similarly, histone arginine/lysine methylation can be the target for the development of therapeutics. The status of histone arginine methylation is intimately involved in gene transcription. Recently, several compounds were found to inhibit protein arginine methyltransferases (PRMTs) [54]. It can also be interesting to explore how this small molecule could be exploited for developing therapeutics. 

As the in vivo introduction of new methyl groups on DNA involves the inhibition of poly(ADP-ribosyl)ation, which in turn can be correlated to a process of chromatin remodeling, parallel experiments were carried out, the only difference being that—for the in vitro reconsti-mtion of chromatin fibers—DNA sequences involved were either unmethylated or methylated with bacterial 5 I methyltransferase. The reconstitution of chromatin fibers was performed by adding either only the core histones or additionally H1 linker histone. 

Enzyme-Based Histone Deacetylase (HDAC) and DNA Methyltransferase (DNMT) Inhibition Data, and Cell-Based p21 Promoter Activity Data, for the Psammaplins (772). 

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