Histone drug target

Despite the complexity of the experiments and the enormous data manipulation necessary, complex biological pathways, as well as new drug targets are being identified by this method. Examples include screens for compounds that arrest cells in mitosis, that block cell migration, and that block the secretory pathway [50], or assays with primary T cells from PLP TCR transgenic mice for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells [51], and identification of small-molecule inhibitors of histone acetyltransferase activity [52]. 

Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21) 7291—7300 Komberg RD and Lorch Y (1999) Twenty-Five years of die nucleosome, fundamental particle of die eukaryote chromosome. Cell 98(3) 285—294... 

Vigushin DM, Coombes RC. (2004) Targeted histone deacetylase inhibition for cancer therapy. Curr Cancer Drug Targets 4 205-218. 

Myzak MC, Dashwood RH. (2006) Histone deacetylases as targets for dietary cancer preventive agents Lessons learned with bntyrate, diallyl disulfide, and snlforaphane. Current Drug Targets 7 443 52. 

Histone Meth /ltransferases as Novel Drug Targets... 

Historically, histone deacetylases (HDACs) were considered as promising drug targets in anticancer therapy due to their regulating role in the histone acetylation status implicated in the epigenetic chromatin control. As a consequence, the potential of HDAC inhibitors was initially attributed to their capacity as chromatin-modulating drugs. 

Chen JS, Faller DV, Spanjaard RA (2003) Short-chain fatty acid inhibitors of histone deacetylases promising anticancer therapeutics Curr Cancer Drug Targets 3(3) 219-236... 

B. Langley, f.M. Gensert, M.F. Beal, R.R. Ratan, Remodeling chromatin and stress resistance in the central nervous system histone deacetylase inhibitors as novel and broadly effective neuroprotective agents, Curr. Drug Targets CNS Neurol. Disord. 2005, 4,41-50. 

The exact role of individual histone acetylations will have to be determined in the context of other modifications and the number of lysine residues effected. However, the general importance of histone acetylation as a regulator for chromatin activity is undisputed. This leads to the intriguing possibility to develop drugs that target histone acetylation for therapeutic purposes. The primary targets for drug development are the histone acetyl transferases (HATs) and the histone deacetylases (HDACs) which introduce and remove histone acetylations [2, 3]. 

Kelly WK, Marks PA (2005) Drug insight histone deacetylase inhibitors - development of the new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Pract Oncol 2 150-157... 

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