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

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

Abstract

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.

Keywords

Anticancer drugs Epigenetics Histone deacetylases Zinc metalloenzymes 

Abbreviations

BCL2

B-cell lymphoma 2

CoREST

Corepressor RE1 silencing transcription factor

EGFR

Epidermal growth factor receptor

EMA

European medicines agency

FDA

Food and drug administration

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HMG-CoA

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

MiDAC

Mitotic deacetylase complex

NcoR

Nuclear receptor corepressor

NODE

Nanog and Oct4-associated deacetylase

NuRD

Nucleosome remodeling deacetylase

PI3K

Phosphatidylinositol 3-kinase

SAHA

Suberoylanilide hydroxamic acid

Sin3

Septation initiation network transcriptional regulatory protein 3

SMRT

Silencing mediator of retinoid and thyroid receptors

Notes

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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