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

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Chemical Epigenetics

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 33))

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.

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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

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  1. School of Pharmacy, University of East Anglia, Norwich, UK

    A. Ganesan

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  1. Sapienza University of Rome, Rome, Italy

    Antonello Mai

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Ganesan, A. (2019). Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery. In: Mai, A. (eds) Chemical Epigenetics. Topics in Medicinal Chemistry, vol 33. Springer, Cham. https://doi.org/10.1007/7355_2019_68

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