Top Med Chem (2020) 33: 1–28
DOI: 10.1007/7355_2019_68
© Springer Nature Switzerland AG 2019
Published online: 14 January 2020
Targeting the Zinc-Dependent Histone
Deacetylases (HDACs) for Drug Discovery
A. Ganesan
Contents
1 The Reversible Acetylation of Lysine Residues in Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 The Zinc-Dependent HDACs . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . 4
3 Hydroxamic Acid HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4 Thiol and Benzamide HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5 Other HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6 Therapeutic Applications Targeting Human HDACs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
7 Therapeutic Applications Targeting Nonhuman HDACs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
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.
A. Ganesan (*)
School of Pharmacy, University of East Anglia, Norwich, UK
e-mail: a.ganesan@uea.ac.uk
DOI: 10.1007/7355_2019_68
© Springer Nature Switzerland AG 2019
Published online: 14 January 2020
Targeting the Zinc-Dependent Histone
Deacetylases (HDACs) for Drug Discovery
A. Ganesan
Contents
1 The Reversible Acetylation of Lysine Residues in Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 The Zinc-Dependent HDACs . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . 4
3 Hydroxamic Acid HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4 Thiol and Benzamide HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5 Other HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
6 Therapeutic Applications Targeting Human HDACs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
7 Therapeutic Applications Targeting Nonhuman HDACs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
8 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
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.
A. Ganesan (*)
School of Pharmacy, University of East Anglia, Norwich, UK
e-mail: a.ganesan@uea.ac.uk