Early in the development of HDAC inhibitors, a common pharmacophore was
proposed consisting of three elements: a binding region, which provides isotype
selectivity (also referred to as “capping group”), a spacer, and an enzyme-inhibiting
group [25]. The “capping group” of the pharmacophore interacts with the rim of the
active site, which is the same area of the enzyme that binds to the peptide backbone
of the protein substrate and, therefore, directs the enzymatic activity toward the right
target. Not surprisingly, this region exhibits structural variability across HDAC
isotypes, which may be exploited for the design of isotype-selective inhibitors
[26]. Since small molecules interact mainly with the active site pocket and only a
small portion of the rim, isotype selectivity has proven elusive for this chemotype.
Thus, peptides have arisen as chemical tools able to cover a larger area of the protein
surface and to establish interactions similar to those of the substrate. In the case of
the enzyme-inhibiting group, it is now known that it drives coordination of the
inhibitor to the catalytic zinc (Zn
2+ ) ion and, therefore, it has been renamed as Zn
2+ -
binding group. Numerous different chemical moieties have been studied for this
purpose, but there is one that stands out: the hydroxamic acid, present in the natural
product 1.1 and in three out of five HDAC inhibitors approved for cancer treatment
including compound 1.2 (Fig. 1) [24].
Potent inhibitors have been created as a combination of a hydroxamic acid Zn
2+ -
binding group, which provides strong binding to the catalytic site, and a cyclic
peptide capping group that adds both potency and selectivity via specific interactions
with the enzyme surface. Also, beyond inhibitors, the fact that HDACs are able to
bind Kac and aliphatic hydroxamic acids likewise offers the possibility of studying
these enzymes with peptides that mimic the interaction with the substrate. Here, we
present a summary of different tools developed for studying and targeting HDACs,
which combine the hydroxamic acid functionality with peptide scaffolds.
Me 2 N
O
N
H
O
1.1, Trichostatin A (TSA)
O
N
H
H
N
HN
1.4, Panobinostat
OH
OH
N
H
S
O O
O
N
H
1.3, Belinostat
OH
H
N
O
N
H
O
1.2, Vorinostat
Suberoylanilide hydroxamic acid (SAHA)
OH
Fig. 1 Chemical structures of a naturally occurring HDAC inhibitor, trichostatin A (1.1), and three
synthetic HDAC inhibitors approved for cancer treatment by the FDA: vorinostat (1.2), belinostat
(1.3), and panobinostat (1.4)
32
C. Moreno-Yruela and C. A. Olsen
proposed consisting of three elements: a binding region, which provides isotype
selectivity (also referred to as “capping group”), a spacer, and an enzyme-inhibiting
group [25]. The “capping group” of the pharmacophore interacts with the rim of the
active site, which is the same area of the enzyme that binds to the peptide backbone
of the protein substrate and, therefore, directs the enzymatic activity toward the right
target. Not surprisingly, this region exhibits structural variability across HDAC
isotypes, which may be exploited for the design of isotype-selective inhibitors
[26]. Since small molecules interact mainly with the active site pocket and only a
small portion of the rim, isotype selectivity has proven elusive for this chemotype.
Thus, peptides have arisen as chemical tools able to cover a larger area of the protein
surface and to establish interactions similar to those of the substrate. In the case of
the enzyme-inhibiting group, it is now known that it drives coordination of the
inhibitor to the catalytic zinc (Zn
2+ ) ion and, therefore, it has been renamed as Zn
2+ -
binding group. Numerous different chemical moieties have been studied for this
purpose, but there is one that stands out: the hydroxamic acid, present in the natural
product 1.1 and in three out of five HDAC inhibitors approved for cancer treatment
including compound 1.2 (Fig. 1) [24].
Potent inhibitors have been created as a combination of a hydroxamic acid Zn
2+ -
binding group, which provides strong binding to the catalytic site, and a cyclic
peptide capping group that adds both potency and selectivity via specific interactions
with the enzyme surface. Also, beyond inhibitors, the fact that HDACs are able to
bind Kac and aliphatic hydroxamic acids likewise offers the possibility of studying
these enzymes with peptides that mimic the interaction with the substrate. Here, we
present a summary of different tools developed for studying and targeting HDACs,
which combine the hydroxamic acid functionality with peptide scaffolds.
Me 2 N
O
N
H
O
1.1, Trichostatin A (TSA)
O
N
H
H
N
HN
1.4, Panobinostat
OH
OH
N
H
S
O O
O
N
H
1.3, Belinostat
OH
H
N
O
N
H
O
1.2, Vorinostat
Suberoylanilide hydroxamic acid (SAHA)
OH
Fig. 1 Chemical structures of a naturally occurring HDAC inhibitor, trichostatin A (1.1), and three
synthetic HDAC inhibitors approved for cancer treatment by the FDA: vorinostat (1.2), belinostat
(1.3), and panobinostat (1.4)
32
C. Moreno-Yruela and C. A. Olsen