Histone therapeutic target

Kramer OH, Gottlicher M, Heinzel T (2001) Histone deacetylase as a therapeutic target. Trends Endocrinol Metab 12 294-300... 

Warrell RP, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998 90 1621-1625. 

Chi P, Allis CD, Wang GG (2010) Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 10 457 69 Herranz M, Esteller M (2006) New therapeutic targets in cancer the epigenetic connection. Clin Transl Oncol 8 242-249... 

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]. 

Figure 4. Therapeutic strategies to counteract CBP loss of function. CBP loss of function leads to a decrease in histone acetylation levels as well as a decrease in CBP-dependent transcription. Two main approaches can be tested to reverse diis process either resetting HAT functionality or resetting global acetylation levels widi die use of HDAC inhibitors. Whereas both strategies would increase histone acetylation levels, HDAC inhibition would act on a broad range of genes, while CBP activation (overexpression or by a pharmacological approach) would specifically target bodi CBP-dependent histone acetylation and transcription. The structure of some of the HDACi that have been tested in different models, such as small fatty acids and hydroxamic acids, are represented in the boxes...

Fig. 1) daily. This resulted in the reduction and disappearance of the myeloblasts, which was reported in the early 1980s. At the time the mechanism of action was unknown, but increased levels of histone acetylation was observed. Based upon this therapeutic response, butyric acid was then studied in clinical trials. Unfortunately, these trials failed to reproduce the early success of butyric acid. This was likely a result of butyric acid s short-half life ( 6m), poor distribution/bioavailability at the target site, and low Cnax (50... 

The dysregulation of transcription has provided a target for therapeutic intervention, and microarray analysis has been used to follow the effect of the drug in the treated samples. For example, acetylation of histones regulates... 

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