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Drug Discov Today. 2015 Jun;20(6):718-35. doi: 10.1016/j.drudis.2015.01.007. Epub 2015 Feb 14.

Histone deacetylases: structural determinants of inhibitor selectivity.

Author information

1
Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
2
Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 183, 41125 Modena, Italy. Electronic address: giulio.rastelli@unimore.it.

Abstract

Histone deacetylases (HDACs) are epigenetic targets with an important role in cancer, neurodegeneration, inflammation, and metabolic disorders. Although clinically effective HDAC inhibitors have been developed, the design of inhibitors with the desired isoform(s) selectivity remains a challenge. Selective inhibitors could help clarify the function of each isoform, and provide therapeutic agents having potentially fewer adverse effects. Crystal structures of several HDACs have been reported, enabling structure-based drug design and providing important information to understand enzyme function. Here, we provide a comprehensive review of the structural information available on HDACs, discussing both conserved and isoform-specific structural and mechanistic features. We focus on distinctive aspects that help rationalize inhibitor selectivity, and provide structure-based recommendations for achieving the desired selectivity.

PMID:
25687212
DOI:
10.1016/j.drudis.2015.01.007
[Indexed for MEDLINE]

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