fluorines and 3.0 Å away from the oxygen of the oxadiazole ring [86]. With these
relatively large distances, metal binding involves weaker electrostatic interactions,
and the Tempero example shows high affinity and selectivity can still be achieved
compared to the direct bidentate coordination typical of hydroxamic acids.
Besides inhibitors 49 and 50, there are compounds with putative zinc-binding
groups whose binding modes are not yet confirmed through X-ray crystallographic
evidence. In the acetyl-lysine mimic 51, a primary amide is the likely zinc binder
and the compound inhibited HDAC1, HDAC2, HDAC3, and HDAC6 at a
submicromolar level [87]. Class I isoform selectivity was also observed with the
tryptophan derivative 52, in which the more common benzamide zinc-binding group
was replaced by a metabolically more stable acyl hydrazide [88]. The metal-binding
properties of tropolones is well-known, and the β-phenyl derivative 53 was reported
to be a remarkably selective subnanomolar HDAC2 inhibitor [89]. A pyrimidobenzothiazine framework has led to selective HDAC8 inhibitors such as 54
[90]. Thiophene 55 is predicted to bind the lipophilic substrate binding tunnel
and was selective for HDAC4 and HDAC6 inhibition [91]. A radically different
mechanism is involved for the hydroxyquinoline 56, a micromolar HDAC5 and
H 2 N
O
N
Cl
Cl
49
HDAC8 IC 50 90 nM
HDAC1 IC 50 >1000 nM
HDAC2 IC 50 >1000 nM
HDAC6 IC 50 >1000 nM
O
H
N
O
N
S
N O
N
CF 3
TMP269
50
HDAC4 IC 50 130 nM
HDAC5 IC 50 80 nM
HDAC7 IC 50 36 nM
HDAC9 IC 50 19 nM
N
NH 2
O
HN
NH
O
NH
MeO
51
HDAC1 IC 50 30 nM
HDAC2 IC 50 160 nM
HDAC3 IC 50 250 nM
HDAC6 IC 50 120 nM
O
H
N N
H
H
N
O
N
H
O
NH
MeO
52
HDAC1 IC 50 10 nM
HDAC2 IC 50 30 nM
HDAC3 IC 50 1.0 nM
O
OH
53
HDAC2 IC 50 0.06 nM
HDAC8 IC 50 1.5 nM
S
N
N
NH
CF 3
54
HDAC5 IC 50 38 nM
HDAC8 IC 50 4.0 nM
S
CF 3
O
HO 2 C
55
HDAC4 IC 50 100 nM
HDAC6 IC 50 70 nM
N
OH
Cl
N
N
N
56
Fig. 16 Examples of atypical HDAC inhibitors
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
17
relatively large distances, metal binding involves weaker electrostatic interactions,
and the Tempero example shows high affinity and selectivity can still be achieved
compared to the direct bidentate coordination typical of hydroxamic acids.
Besides inhibitors 49 and 50, there are compounds with putative zinc-binding
groups whose binding modes are not yet confirmed through X-ray crystallographic
evidence. In the acetyl-lysine mimic 51, a primary amide is the likely zinc binder
and the compound inhibited HDAC1, HDAC2, HDAC3, and HDAC6 at a
submicromolar level [87]. Class I isoform selectivity was also observed with the
tryptophan derivative 52, in which the more common benzamide zinc-binding group
was replaced by a metabolically more stable acyl hydrazide [88]. The metal-binding
properties of tropolones is well-known, and the β-phenyl derivative 53 was reported
to be a remarkably selective subnanomolar HDAC2 inhibitor [89]. A pyrimidobenzothiazine framework has led to selective HDAC8 inhibitors such as 54
[90]. Thiophene 55 is predicted to bind the lipophilic substrate binding tunnel
and was selective for HDAC4 and HDAC6 inhibition [91]. A radically different
mechanism is involved for the hydroxyquinoline 56, a micromolar HDAC5 and
H 2 N
O
N
Cl
Cl
49
HDAC8 IC 50 90 nM
HDAC1 IC 50 >1000 nM
HDAC2 IC 50 >1000 nM
HDAC6 IC 50 >1000 nM
O
H
N
O
N
S
N O
N
CF 3
TMP269
50
HDAC4 IC 50 130 nM
HDAC5 IC 50 80 nM
HDAC7 IC 50 36 nM
HDAC9 IC 50 19 nM
N
NH 2
O
HN
NH
O
NH
MeO
51
HDAC1 IC 50 30 nM
HDAC2 IC 50 160 nM
HDAC3 IC 50 250 nM
HDAC6 IC 50 120 nM
O
H
N N
H
H
N
O
N
H
O
NH
MeO
52
HDAC1 IC 50 10 nM
HDAC2 IC 50 30 nM
HDAC3 IC 50 1.0 nM
O
OH
53
HDAC2 IC 50 0.06 nM
HDAC8 IC 50 1.5 nM
S
N
N
NH
CF 3
54
HDAC5 IC 50 38 nM
HDAC8 IC 50 4.0 nM
S
CF 3
O
HO 2 C
55
HDAC4 IC 50 100 nM
HDAC6 IC 50 70 nM
N
OH
Cl
N
N
N
56
Fig. 16 Examples of atypical HDAC inhibitors
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
17