pp 1-27 | Cite as

Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery

  • A. GanesanEmail author
Part of the Topics in Medicinal Chemistry book series


In humans, the zinc-dependent histone deacetylases (HDACs) are a family of 11 nonredundant isoforms that catalyze the dynamic reversal of posttranslationally modified acyl-lysine residues back to lysine. At the epigenetic level, HDACs have a critical gene silencing effect, promoting the compaction of histone tails with DNA to prevent transcription. In addition, HDACs deacylate many nonhistone substrates in diverse cellular compartments to profoundly influence protein structure and function. While the action of HDACs is indispensable to normal physiology, their abnormal overexpression is linked to the majority of human diseases. Consequently, the inhibition of HDACs has become a valuable target for therapeutic applications. Numerous potent small molecules are known, of both natural product and synthetic origin, that inhibit HDACs, primarily by reversibly interacting with the zinc cation within the enzyme active site. At the present time, five such HDAC inhibitors have received regulatory approval for the treatment of hematological cancers. This review focuses on the typical zinc-binding groups employed in HDAC inhibitors and the major advances within each class in terms of potency, isoform selectivity, and clinical applications.


Anticancer drugs Epigenetics Histone deacetylases Zinc metalloenzymes 



B-cell lymphoma 2


Corepressor RE1 silencing transcription factor


Epidermal growth factor receptor


European medicines agency


Food and drug administration


Histone acetyltransferase


Histone deacetylase


3-Hydroxy-3-methyl-glutaryl-coenzyme A


Mitotic deacetylase complex


Nuclear receptor corepressor


Nanog and Oct4-associated deacetylase


Nucleosome remodeling deacetylase


Phosphatidylinositol 3-kinase


Suberoylanilide hydroxamic acid


Septation initiation network transcriptional regulatory protein 3


Silencing mediator of retinoid and thyroid receptors


Compliance with Ethical Standards

Conflict of Interest: Author declares that he has no conflict of interest.

Ethical approval: Not applicable.


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© Springer Nature Switzerland AG  2019

Authors and Affiliations

  1. 1.School of PharmacyUniversity of East AngliaNorwichUK

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