A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo

Article abstract of DOI:10.1021/jm800079s

Histone deacetylase (HDAC) inhibitors offer a promising strategy for cancer therapy, and the first generation HDAC inhibitors are currently in the clinic. Entirely novel ketone HDAC inhibitors have been developed from the cyclic tetrapeptide apicidin. These compounds show class I subtype selectivity and levels of cellular activity comparable to clinical candidates. A representative example has demonstrated tumor growth inhibition in a human colon HCT-116 carcinoma xenograft model comparable to known inhibitors.

Full text of DOI:10.1021/jm800079s

2350
J. Med. Chem. 2008, 51, 2350–2353
A Novel Series of Potent and Selective
Ketone Histone Deacetylase Inhibitors with
Antitumor Activity in Vivo
Philip Jones,* Sergio Altamura, Raffaele De Francesco,
Odalys Gonzalez Paz, Olaf Kinzel, Giuseppe Mesiti,
Edith Monteagudo, Giovanna Pescatore, Michael Rowley,
Maria Verdirame, and Christian Steinku¨hler
IRBM/Merck Research Laboratories, Via Pontina km 30,600,
00040 Pomezia, Italy
ReceiVed January 26, 2008
Abstract: Histone deacetylase (HDAC) inhibitors offer a promising
strategy for cancer therapy, and the first generation HDAC inhibitors
are currently in the clinic. Entirely novel ketone HDAC inhibitors have
been developed from the cyclic tetrapeptide apicidin. These compounds
show class I subtype selectivity and levels of cellular activity com-
parable to clinical candidates. A representative example has demon-
strated tumor growth inhibition in a human colon HCT-116 carcinoma
xenograft model comparable to known inhibitors.
Aberrant regulation of gene expression is at the basis of many
human diseases and notably many forms of cancer.1 Yet attempts
to pharmacologically target transcription complexes have been
to date limited. In chromatin, DNA is wrapped around a core
of eight histones to form nucleosomes, and these core histones
have long N-terminal extensions that undergo extensive post-
translational modifications including not only acetylation, meth-
ylation, and phosphorylation but also ubiquitination, sumoyla-
tion, and ADP-ribosylation.2,3 The discovery that inhibition of
chromatin modifying enzymes modulates transcription has
allowed the development of novel pharmacologic agents.4
The acetylation status of lysine residues in these nucleosomal
histone proteins is tightly controlled by two counteracting
enzyme families, the histone acetyl transferases (HATs) and
the histone deacetylases (HDACs).a The latter family is divided
into four groups: classes I, II, and IV are closely related Zn-
dependent enzymes, while the sirtuins, or class III, are structur-
ally unrelated NAD-dependent deacetylases.5 The presence of
acetyl groups on these lysine residues neutralizes the positive
charges of the histone tails, thereby decreasing interactions with
DNA, relaxing the chromatin, and allowing access to transcrip-
tion factors.6 In contrast, removal of the acetyl groups from
these Ac-lysines represses transcription by facilitating the
interactions of ε-amino group with the DNA thereby condensing
the chromatin. In addition to histones, a number of other proteins
also undergo acetylation. Generally, acetylation has profound
influences on their metabolic stability or biological function and
thus can be regarded as a post-translational control mechanism
of function.7
Figure 1. Known HDAC inhibitors.
Figure 2. Activity of bis-amide HDAC inhibitors.26
angiogenesis.7–9 However, the precise mechanism of action
remains unclear.7 Recently, vorinostat (1) (Zolinza, formerly
known as SAHA) was approved for the treatment of the
cutaneous manifestations of advanced CTCL that has relapsed
or progressed on or following two or more systemic therapies.10
In addition, there are several HDACi’s in clinical trials, showing
efficacy in hematological and solid malignancies.11
Histone deacetylase inhibitors (HDACi’s) are emerging as a
new class of anticancer agents and have been shown to alter
gene transcription and exert antitumor effects such as growth
arrest, differentiation, apoptosis, and inhibition of tumor
To date these HDACi’s belong to several distinct structural
classes (Figure 1).8 Hydroxamic acids like 1,12 2,13 and 314 have
been reported, although these are typically unselective HDACi’s.
The aminobenzamides 415 and 616 have advanced into studies
in man, and more recently, bis-aryl derivatives like 5 have been
disclosed as selective HDAC 1 and 2 inhibitors.17 Other classes
* To whom correspondence should be addressed. Phone: (+39)
0691093559. Fax: (+39) 0691093654. E-mail: philip_jones@merck.com.
a Abbreviations: HAT, histone acetyl transferases; HDAC, histone
deacetylases; HDACi, histone deacetylase inhibitor; ZBG, zinc binding
group; HRE, human renal epithelial; MTD, maximum tolerated dose; TGI,
tumor growth inhibition.
10.1021/jm800079s CCC: $40.75
2008 American Chemical Society
Published on Web 03/28/2008

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 8 2351
Scheme 1a
Figure 3. Plasma stability of 16 following incubations in mouse (]),
rat (b), dog (2), and human (0) plasma for 24 h at 37 °C.
Figure 4. (A, left) X-ray crystal structure of HDAC 8 and bound
inhibitor showing H-bonding to asp-101.27 (B, right) Docking studies
of HDAC 1 and 17 showing potential for H-bonding to asp-99 from
the bioisoteric imidazole.
include short chain fatty acids, like valproic acid (7),18 and
electrophilic ketones such as 8.19 Furthermore, natural products
are known to inhibit deacetylase activity, including among others
apicidin (9),20 FK-228 (10),21 HC-toxin (11),22 FR235222 (12),23
and azumamide A and E (13 and 14),24 and synthetic analogues
have been described.25
Herein efforts to develop a novel class of HDACi’s are
described, targeting a second generation inhibitor with better
potency and selectivity between HDAC isoforms.
a Reagents and conditions: (a) (i) ClCOCOCl, DCM; (ii) MeOMe-
NH2+Cl-, Et3N, DCM; (b) RMgBr, THF, 0 °C; (c) NaI, acetone, ∆; (d)
HO(CH2)2OH, cat. PTSA, toluene, ∆; (e) 23, BuLi, THF, -78 °C; then
22, -78 °C to room temp; (f) H3O+/THF; (g) Boc2O, NaHCO3, dioxane/
H2O; (h) LiOH, THF/H2O; (i) (i) Cs2CO3, EtOH; (ii) PhCOCH2Br, DMF;
(iii) NH4OAc, xylene, ∆; (j) TFA, DCM; (k) (5-methoxy-2-methyl-1H-
Recently, initial efforts to that goal have been described
whereby the natural product apicidin was selected as a suitable
starting point.26 This compound contains an ethyl ketone as
potential zinc binding group (ZBG), a long alkyl chain, and
the cyclic tetrapeptide that interacts with the surface of the
HDAC. Despite the unusual ZBG, it is a relatively potent HDAC
1 inhibitor, IC50 ) 44 nM, and displays good antiproliferation
activity against cervical cancer HeLa cells, IC50 ) 290 nM.
Directed screening of the sample collection looking for com-
pounds containing the unusual L-Aoda amino acid identified a
more tractable lead which was optimized into potent, low
molecular weight, selective, non-hydroxamic acid HDACi’s
exemplified by 15 (Figure 2). This compound inhibits HDACs
1, 2, 3, and 6 and shows good antiproliferative activity, for
instance, HeLa cells IC50 ) 430 nM.
i
indol-3-yl)acetic acid, EDC, HOBT, Et3N; (l) (i) BuOCOCl, THF; (ii)
ClC6H3(NH2)2, THF; (m) AcOH, 65 °C.
revealed that the compound was unstable in rat plasma, with
the anilide bond being readily hydrolyzed (Figure 3). Similar
observations were seen in mouse plasma, although the com-
pound was stable in dog and human plasma. Further analogues
from this bis-amide series of HDAC inhibitors were screened,
and the vast majority was susceptible to hydrolysis. Given that
good exposure in rodents would be a necessity for the develop-
ment of these HDAC inhibitors, in order to perform efficacy
and safety studies, attention therefore turned to replacement of
the labile bond with a suitable bioisostere.
In an effort to demonstrate in vivo antitumor activity with
an HDAC inhibitor from this novel structural class, the
microsomal stability of these compounds was determined.
Unfortunately, 15 proved to be rapidly turned over in rat liver
microsomes, and high intrinsic clearance in microsomes proved
to be an issue with this class of compounds. The quinoline 16,
while maintaining enzyme activity, HDAC 1 IC50 ) 140 nM,
and low micromolar cellular activity PRO(HeLa) ) 2 µM,
showed improved microsomal stability and was tested in vivo.
Unfortunately, following iv administration in rats at 3 mg/kg
16 proved to have low exposure (AUC ) 0.05 µM·h) and to
be cleared rapidly, Cl > 150 (mL/min)/kg. Further investigation
X-ray crystal structures of a related hydroxamic acid bound
to HDAC 8 revealed that the two amide bonds of these inhibitors
are involved in forming two hydrogen bonds to aspartic acid-
101 on the rim of the binding pocket (Figure 4A).27 This residue
is conserved in all class I and II HDACs, with the exception of
HDAC 11, and is believed to be crucial for substrate recognition.
Replacement bioisosteres were designed to maintain this
interaction. Accordingly 4-phenylimidazole 17 and the corre-
sponding benzimidazole 18 were targeted. Both compounds
should be capable of forming H-bonds to this aspartic acid
present at the mouth of the binding cavity as shown by docking
studies (Figure 4B).

2352 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 8
Letters
Table 1. Activity on the HDAC Isoforms, IC50 (nM)a
compd HDAC 1 HDAC 2 HDAC 3 HDAC 4GOF28 HDAC 4WT28
HDAC 5
HDAC 6
HDAC 7
HDAC 8
1
4
17
18
19
30
120
59
670
26
82
250
110
880
59
57
400
120
1000
48
540
>10 µM
6000
4200
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM
40% inh at 10 µM 43
>10 µM 1700
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM
>10 µM >10 µM
>10 µM >5 µM
>10 µM >10 µM
340
970
40% inh at 10 µM >10 µM 40% inh at 10 µM
a IC50 values are averaged from multiple determinations (n g 2), and the standard derivations are <30% of the mean.
Table 2. Antiproliferation Activity against Various Cell Lines, IC50
(nM)a
cervical
HeLa
colon
lung kidney ovarian human renal
compd
HCT116 A549 G401 A2780 epithelial cells
1
4
17
18
19
460
1800
880
3100
340
1000
700
500
4200
330
1800
1200
6300
8200
5200
1000
1300
960
7500
250
2600
3000
2200
11000
420
14000
>20000
16000
41000
5300
a IC50 values are averaged from multiple determinations (n g 2), and
the standard derivations are <30% of the mean.
The desired compounds were readily prepared as shown in
Scheme 1 from the key N-Boc amino acid ester 25. This was
prepared using Scho¨llkopf chemistry, whereby alkylation of the
protected alkyl iodide 22, readily synthesized without chroma-
tography, gave protected amino acids 25 in 58% yield. Hy-
drolysis of the methyl ester and alkylation with the bromoac-
etophenone gave the key cyclization precursor. Refluxing this
keto-ester in xylene in the presence of a large excess of
ammonium acetate gave rise to the desired 4-phenylimidazole
27. Finally, deprotection and coupling yielded 17. In a similar
manner, the benzimidazole 18 was prepared from 25 by Boc-
deprotection and coupling to the substituted indol-3-ylacetic
acid. Subsequent hydrolysis and coupling of the resulting acid
to 4-chloro-1,2-benzenediamine followed by cyclization with
AcOH at 65 °C gave 18.
Both compounds maintained good HDAC 1 inhibition (Table
1), with the 4-phenylimidazole 17 showing approximately 10-
fold better activity than benzimidazole 18, with IC50 ) 59 and
670 nM, respectively. The improved activity of 17 was
recapitulated on the other class I subtypes where 17 displayed
8-fold higher potency than 18 on HDAC 2 (IC50 ) 110 vs 880
nM) and HDAC 3 (IC50 ) 120 vs 1000 nM). As observed
previously in the bis-amide class of HDACi’s,26 17 proved to
be a selective HDACs 1, 2, and 3 inhibitor, with weaker HDAC
6 activity and no inhibition on HDACs 4, 5, and 7 at 10 µM.
Furthermore, 17 gave no inhibition of HDAC 8 at 5 µM, in
contrast to 1 with IC50 ) 1.7 µM.
With these encouraging enzymatic inhibitory properties, their
cellular activity against a broad panel of human cancer cell lines
was evaluated, including cervical, colon, kidney, ovarian, and
lung cancer cell lines (Table 2). While 17 displayed submicro-
molar antiproliferation activity against HeLa, HCT116, and
G401 cancer cell lines, IC50 ) 880, 500, and 960 nM, the
ovarian A2780 and lung A549 cell lines proved to be more
resistant, and micromolar activity was observed. These results
mirror the data seen with the prototypical HDAC inhibitors, 1
and 4, where the A2780 and A549 cell lines are more resistant.
In contrast, the benzimidazole 18, in line with the reduced
enzyme activity, displayed weaker antiproliferative effects with
IC50 values in the low micromolar range on the panel of cell
lines. All the HDACi’s showed good selectivity for tumor over
normal cells, as demonstrated by the weaker growth inhibition
seen against human renal epithelial (HRE) cells. For instance,
1 and 17 have average IC50 values of 1.4 and 1.9 µM against
Figure 5. Human HCT116 colon cancer xenograft model in nude mice
(15 per group): 1 (2), 4 (]), 17 (b), and vehicle (0) administered ip
once a day, 5 day/week.
the five tumor cell lines, while they display IC50 values of 14
and 16 µM on HRE cells.
Given the instability seen with 16 and related compounds in
rodent plasma, 17 and 18 were subjected to plasma stability
studies. In contrast to the bis-amides, both displayed excellent
stabilities and no degradation was seen at 37 °C in mouse, rat,
dog, or human plasma for 4 h. Despite the finding that both
compounds were turned over rapidly in rat and human liver
microsomes, Clint > 400 (µL/min)/mg P, given the interest in
this new class of inhibitors 17 was subjected to a rat PK study.
Unsurprisingly, given the high microsomal turnover, 17 showed
high clearance in vivo Cl ) 80 (mL/min)/kg, short terminal
half-life t1/2 ) 1.3 h, and modest oral bioavailability F ) 15%.
With the encouraging cellular activity and acceptable rat
pharmacokinetic profile, it was decided to evaluate 17 in an in
vivo efficacy study, a human colon HCT-116 carcinoma
xenograft model. This novel class of HDACi was profiled
alongside the benchmark compounds 1 and 4. In preliminary
studies, the maximum tolerated dose (MTD) of all three
compounds was determined following intraperitoneal once daily
dosing for 1 week, as defined by no mortality and body weight
loss less than 10%. MTD was established to be 100 mg/kg for
1, 25 mg/kg for 4, and 60 mg/kg for 17. A quantity of 4 × 106
cells were inoculated subcutaneously in the flank of female mice,
and tumors were allowed to grow for 14 days to an average
size of 150 mm3 prior to the initiation of treatment. Animals
were then treated daily intraperitoneally at the MTD for 5 days/
week for 21/2 weeks. Dose dependent tumor growth inhibition
(TGI) was seen with 17 (Figure 5). In fact, at 60 mg/kg, 17
showed similar levels of tumor growth inhibition (TGI ) 59%)
compared to 1 and 4 dosed at their MTDs (TGI ) 56% and
69%, respectively). These doses were well tolerated, and less
than 10% body weight loss was observed with all compounds.
To our knowledge this is the first example of a small molecule
alkyl ketone HDACi demonstrating efficacy in xenograft
studies.29
Encouraged by this result and the observation that alkyl
ketones are indeed able to cause tumor growth inhibition in vivo,

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 8 2353
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and 3 and also in antiproliferation assays, compared to 17.
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molecule selective HDAC inhibitors have been developed. These
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existing clinical candidates. Furthermore, variations in the ketone
zinc binding group have been demonstrated to fine-tune the
isoform profile, thereby abolishing activity on HDAC 6, thus
yielding selective HDAC 1, 2, and 3 inhibitors. A representative
example 17 has been demonstrated to cause tumor growth
inhibition in a xenograft model.
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of this work.
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