inhibited at a micromolar level. The compound design takes advantage of a “lower
pocket” present in the class IIa enzymes that accommodates the phenyl ring, and this
was corroborated by X-ray structures of enzyme-inhibitor complexes.
Besides isoform discrimination, two alternative approaches for HDAC drug
discovery involve the use of prodrugs or multitarget inhibitors with a dual mechanism of action. Chroma’s tefinostat (23, Fig. 10) is relatively nonselective but
accumulates less in normal cells due to secretion through efflux pumps. In the
liver, human carboxylesterase-1 hydrolyses the cyclopentyl ester to give a poorly
diffusible ionized carboxylic acid, enabling selective targeting to liver cancers for
which the compound is currently undergoing clinical trials [50]. The hydroxamic
acid itself can be converted to a prodrug form to improve bioavailability. A recent
example with belinostat (24) was shown to possess higher activity compared to the
parent drug in a MCF-7 breast cancer tumor xenograft animal model [51]. Meanwhile, the simplicity of the HDAC pharmacophore suggests the “cap” can incorporate the pharmacophore for a second orthogonal target. Inhibitors have been
successfully developed that are dual inhibitors of HDACs and kinase inhibitors as
well as other enzymes such as HMG-CoA reductase, phosphodiesterase type
5, DNA topoisomerase, and receptors including the vitamin D receptor, retinoid
X receptor, and estrogen receptor [52, 53]. Two examples from Curis are currently
in clinical trials: CUDC-101 (25) for dual HDAC/EGFR inhibition and CUDC-907
(26) for dual HDAC/PI3K inhibition [54, 55].
CUDC-101
25
HDAC IC 50 4.4 nM
EGFR 1C 50 2.4 nM
H
N
N
H
OH
O
O
H
N
O
O
N
H
O
B O
O
tefinostat
23
belinostat prodrug
24
N
N
NH
OMe
O
N
H
O
OH
N
N
S
N
N
O
N
N
MeO
N
O
N
H
OH
CUDC-907
26
HDAC1 IC 50 1.7 nM
HDAC6 IC 50 27 nM
PI3K1C 50 19 nM
O
S
N
H O
O
Fig. 10 Examples of prodrug and dual mechanism hydroxamic acid HDAC inhibitors
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
11
pocket” present in the class IIa enzymes that accommodates the phenyl ring, and this
was corroborated by X-ray structures of enzyme-inhibitor complexes.
Besides isoform discrimination, two alternative approaches for HDAC drug
discovery involve the use of prodrugs or multitarget inhibitors with a dual mechanism of action. Chroma’s tefinostat (23, Fig. 10) is relatively nonselective but
accumulates less in normal cells due to secretion through efflux pumps. In the
liver, human carboxylesterase-1 hydrolyses the cyclopentyl ester to give a poorly
diffusible ionized carboxylic acid, enabling selective targeting to liver cancers for
which the compound is currently undergoing clinical trials [50]. The hydroxamic
acid itself can be converted to a prodrug form to improve bioavailability. A recent
example with belinostat (24) was shown to possess higher activity compared to the
parent drug in a MCF-7 breast cancer tumor xenograft animal model [51]. Meanwhile, the simplicity of the HDAC pharmacophore suggests the “cap” can incorporate the pharmacophore for a second orthogonal target. Inhibitors have been
successfully developed that are dual inhibitors of HDACs and kinase inhibitors as
well as other enzymes such as HMG-CoA reductase, phosphodiesterase type
5, DNA topoisomerase, and receptors including the vitamin D receptor, retinoid
X receptor, and estrogen receptor [52, 53]. Two examples from Curis are currently
in clinical trials: CUDC-101 (25) for dual HDAC/EGFR inhibition and CUDC-907
(26) for dual HDAC/PI3K inhibition [54, 55].
CUDC-101
25
HDAC IC 50 4.4 nM
EGFR 1C 50 2.4 nM
H
N
N
H
OH
O
O
H
N
O
O
N
H
O
B O
O
tefinostat
23
belinostat prodrug
24
N
N
NH
OMe
O
N
H
O
OH
N
N
S
N
N
O
N
N
MeO
N
O
N
H
OH
CUDC-907
26
HDAC1 IC 50 1.7 nM
HDAC6 IC 50 27 nM
PI3K1C 50 19 nM
O
S
N
H O
O
Fig. 10 Examples of prodrug and dual mechanism hydroxamic acid HDAC inhibitors
Targeting the Zinc-Dependent Histone Deacetylases (HDACs) for Drug Discovery
11