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.

Histone deacetylases: Structural determinants of inhibitor selectivity / Micelli, Carmina; Rastelli, Giulio. - In: DRUG DISCOVERY TODAY. - ISSN 1359-6446. - ELETTRONICO. - 20:6(2015), pp. 718-735. [10.1016/j.drudis.2015.01.007]

Histone deacetylases: Structural determinants of inhibitor selectivity

Micelli, Carmina;Rastelli, Giulio
2015

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.
2015
14-feb-2015
20
6
718
735
Histone deacetylases: Structural determinants of inhibitor selectivity / Micelli, Carmina; Rastelli, Giulio. - In: DRUG DISCOVERY TODAY. - ISSN 1359-6446. - ELETTRONICO. - 20:6(2015), pp. 718-735. [10.1016/j.drudis.2015.01.007]
Micelli, Carmina; Rastelli, Giulio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1079988
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