DNMTs and HDACs

Benzamides constitute a fourth dass of HDAC inhibitors. One example, MS-275, is a phenylenediamine derivative that exhibits robust HDAC inhibition in patients with advanced myeloid leukemia as well as refractory solid tumors or lymphoma in Phase I studies [72]. MS-275 is currently in Phase II trials. In a recent study aimed at optimizing the benzamide scaffold, several bis-(aryl) type analogs were synthesized and evaluated for their activity against a panel of HDACs [85]. Moradei et al. found that a thienyl substitution para to the free amino group in the phenylenediamine core rendered inhibitors specific for HDACsl, 2 with potency superior to that of MS-275. Isoform-specific inhibitors should aid in dissecting the roles of HDACs in normal cellular fundioning and cancer. 

We thank Josh Coon for helpful comments. Epigenetic research in the Denu laboratory is supported by NIH grants GM065386 and GM059785. 

and Jones, P.A. (2006) Epigenetic therapy of cancer past, present and future. Nature Reviews. Drug Discovery, 5, 37-50. 

2 Ruthenburg, A.J., Li, H., Patel, D.J. and Allis, C.D. (2007) Multivalent engagement of chromatin modifications by linked binding modules. Nature Reviews. Molecular Cell Biology, 8, 983-994. 

3 Klose, R.). and Bird, A.P. (2006) Genomic DNA methylation the mark and its mediators. Trends in Biochemical Sciences, 31, 89-97. 

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Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

The DNMTs at least partially account for the interaction of DNA methylation with histone modification as these enzymes are able to directly recruit histone deacetylases (HDACs) and this is achieved by binding methylated C ( etQ binding proteins such as MeCP2, MBD1, MBD2, and MBD3 (detailed reviews in Refs. 24 and 25). 

Table 1 The In Vitro Effects of HDAC and DNMT Inhibitors...

Histone deacetylases (HDACs), histone acetyltransferases (HMTs), histone demethylases (HDMTs), protein arginine methyltransterases (PRMTs), histone arginine demethylases (HADs), and DNA methyltransferases (DNMTs). 

Recently, psammaplins were reported as potent histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors (see Table X) (772). Eleven psammaplins (see Table X), isolated from the sponge Pseudoceratina purpurea, were tested in the histone deacetylase (HDAC) enzyme assay at concentrations ranging from 16 nM to 10 pM, and the data obtained were compared to that of two standards, trichostatin A 300) and trapoxin A 301). There were three psammaplin derivatives whose IC50 values were in a... 

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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