group [78]. As butyrate suffers from a short in vivo half-life [79], clinical trials have
focused on prodrugs such as Pivanex (41, Fig. 14) or the repurposing of the wellestablished antiepileptic drug valproic acid (42). However, the low potency of such
monodentate short chain carboxylic acids (millimolar IC 50 against HDAC enzymes)
compared to other zinc-binding groups is a challenge for therapeutic applications,
and none have received regulatory approval. At the preclinical stage, the marine
depsipeptide natural product azumamide E (43) is a rare example of a carboxylic
acid HDAC inhibitor with submicromolar potency [80]. In this case, the active site
zinc coordination is presumably augmented by additional interactions from the
macrocyclic cap to improve binding affinity.
Hydroxamic acids, thiols, benzamides, and carboxylic acids are the only four
zinc-binding groups incorporated into HDAC inhibitors that have progressed to
clinical investigation. Besides these motifs, ketones and derivatives thereof are an
important zinc-binding group at the preclinical stage. Their presence was first
observed in a family of fungal toxin cyclic tetrapeptide natural products such as
trapoxin A (44, Fig. 15), AS1387392 (45) and apicidin (46) that are potent inhibitors
of class I HDAC isoforms. Trapoxin A was originally believed to be an irreversible
inhibitor that undergoes epoxide ring opening by a nucleophilic residue in the active
site. However, a recent X-ray structure of the natural product bound to HDAC8
Table 5 The IC 50 values of
entinostat and tucidinostat
against individual isoforms,
based on data provided in
reference [75]
Isoform
Entinostat IC 50 (nM)
Tucidinostat IC 50 (nM)
HDAC1
260
100
HDAC2
310
160
HDAC3
500
70
HDAC8
>1,000
730
HDAC4
>1,000
>1,000
HDAC5
>1,000
>1,000
HDAC7
>1,000
>1,000
HDAC9
>1,000
>1,000
HDAC6
>1,000
>1,000
HDAC10
250
80
HDAC11
650
430
O
OH
valproic acid
42
O
O
Pivanex
41
O
O
NH
NH
HN
HN
O
O
O
O
OH
O
azumamide E
43
HDAC1 IC 50 120 nM
HDAC6 IC 50 860 nM
Fig. 14 Examples of carboxylic acid HDAC inhibitors
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
15
focused on prodrugs such as Pivanex (41, Fig. 14) or the repurposing of the wellestablished antiepileptic drug valproic acid (42). However, the low potency of such
monodentate short chain carboxylic acids (millimolar IC 50 against HDAC enzymes)
compared to other zinc-binding groups is a challenge for therapeutic applications,
and none have received regulatory approval. At the preclinical stage, the marine
depsipeptide natural product azumamide E (43) is a rare example of a carboxylic
acid HDAC inhibitor with submicromolar potency [80]. In this case, the active site
zinc coordination is presumably augmented by additional interactions from the
macrocyclic cap to improve binding affinity.
Hydroxamic acids, thiols, benzamides, and carboxylic acids are the only four
zinc-binding groups incorporated into HDAC inhibitors that have progressed to
clinical investigation. Besides these motifs, ketones and derivatives thereof are an
important zinc-binding group at the preclinical stage. Their presence was first
observed in a family of fungal toxin cyclic tetrapeptide natural products such as
trapoxin A (44, Fig. 15), AS1387392 (45) and apicidin (46) that are potent inhibitors
of class I HDAC isoforms. Trapoxin A was originally believed to be an irreversible
inhibitor that undergoes epoxide ring opening by a nucleophilic residue in the active
site. However, a recent X-ray structure of the natural product bound to HDAC8
Table 5 The IC 50 values of
entinostat and tucidinostat
against individual isoforms,
based on data provided in
reference [75]
Isoform
Entinostat IC 50 (nM)
Tucidinostat IC 50 (nM)
HDAC1
260
100
HDAC2
310
160
HDAC3
500
70
HDAC8
>1,000
730
HDAC4
>1,000
>1,000
HDAC5
>1,000
>1,000
HDAC7
>1,000
>1,000
HDAC9
>1,000
>1,000
HDAC6
>1,000
>1,000
HDAC10
250
80
HDAC11
650
430
O
OH
valproic acid
42
O
O
Pivanex
41
O
O
NH
NH
HN
HN
O
O
O
O
OH
O
azumamide E
43
HDAC1 IC 50 120 nM
HDAC6 IC 50 860 nM
Fig. 14 Examples of carboxylic acid HDAC inhibitors
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
15