Targeting Class I Histone Deacetylases in a "Complex" Environment. (April 2017)

• Record Type: Journal Article
• Authors: Millard, Christopher J.; Watson, Peter J.; Fairall, Louise; Schwabe, John W.R.
• Is Part Of: Trends in pharmacological sciences. Volume 38:Number 4(2017)
• Page Start: 363
• Page End: 377
• Publication Date: 2017-04
• Subjects: histone deacetylases -- transcription repression -- co-repressor complexes -- gene regulation -- HDAC inhibitors -- inositol phosphates; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2016.12.006
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer's disease, and Friedreich's ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Designing isoform-selective inhibitors has proven challenging due to similarities in the structure and chemistry of HDAC active sites. However, the fact that HDACs 1, 2, and 3 are recruited to several large multi-subunit complexes, each with particular biological functions, raises the possibility of specifically inhibiting individual complexes. This may be assisted by recent structural and functional information about the assembly of these complexes. Here, we review the available structural information and discuss potential targeting strategies. Trends: All currently licenced HDAC drugs (HDAC inhibitors) are pan-inhibitors that work by targeting the active-site zinc. HDAC inhibitors are used in the clinic as anticancer therapeutics, but due to their nonselective nature, many patients experience significant side effects. The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients. HDACs 1, 2, and 3 are of particular interest as they are recruited to multiprotein complexes to mediate gene transcription. As part of these complexes, the HDACs become maximally activated, and are targeted to specific genes. The recruitment of class I HDACs into multiprotein assemblies opens up the possibility of using alternative strategies to develop complex-specific HDAC inhibitors.