New thiazole carboxamides as potent inhibitors of Akt kinases

Article abstract of DOI:10.1016/j.bmcl.2011.11.080

A new series of 2-substituted thiazole carboxamides were identified as potent pan inhibitors against all three isoforms of Akt (Akt1, Akt2 and Akt3) by systematic optimization of weak screening hit N-(1-amino-3-phenylpropan-2-yl)- 2-phenylthiazole-5-carboxamide (1). One of the most potent compounds, 5m, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC₅₀ values of 25, 196 and 24 nM, respectively. The compound also potently inhibited the phosphorylation of downstream MDM2 and GSK3β proteins, and displayed strongly antiproliferative activity in prostate cancer cells. The inhibitors might serve as lead compounds for further development of novel effective anticancer agents.

Full text of DOI:10.1016/j.bmcl.2011.11.080

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1208–1212
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New thiazole carboxamides as potent inhibitors of Akt kinases
Shaohua Chang a,b, Zhang Zhang a, Xiaoxi Zhuang a, Jinfeng Luo a, Xianwen Cao c, Honglin Li c,
Zhengchao Tu a, Xiaoyun Lu a, Xiaomei Ren a, Ke Ding a,
⇑
a Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
No. 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, China
b Graduate School of Chinese Academy of Sciences, # 19 Yuquan Road, Beijing 100049, China
c Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2011
Revised 31 October 2011
Accepted 19 November 2011
Available online 30 November 2011
A new series of 2-substituted thiazole carboxamides were identified as potent pan inhibitors against
all three isoforms of Akt (Akt1, Akt2 and Akt3) by systematic optimization of weak screening hit
N-(1-amino-3-phenylpropan-2-yl)-2-phenylthiazole-5-carboxamide (1). One of the most potent com-
pounds, 5m, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC50 values of 25, 196 and
24 nM, respectively. The compound also potently inhibited the phosphorylation of downstream MDM2
and GSK3b proteins, and displayed strongly antiproliferative activity in prostate cancer cells. The inhib-
itors might serve as lead compounds for further development of novel effective anticancer agents.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Akt kinase
Inhibitors
Thiazole carboxamides
Akt, also known as protein kinase B (PKB), is a class of
serine/threonine kinases and consists of three isoforms, Akt1
(PKBa), Akt2 (PKBb) and Akt3 (PKBc). Although the three isoforms
dose-dependently inhibited the enzymatic activity of Akt1 with
an IC50 value of 40.0 M. Interestingly, hydroxyl substituted deriv-
atives 2 and 3 displayed obviously improved activities against Akt1
(IC50 values of 8.0 and 1.7 M, respectively), which might serve as
new promising lead compounds for further studies. A structural
feature analysis suggested that compounds 1, 2 and 3 shared great
similarity with a well characterized pan Akt inhibitor 4.10 There-
fore, compound 1 was extensively optimized by taking advantage
of the structure–activity relationship information of inhibitor 4
(Fig. 1).
Herein, we report the structural optimization of 2-substituted
thiazole carboxamide derivatives as new potent Akt inhibitors.
The synthesis of 2-aminopyrimidine thiazole carboxamide
derivatives is depicted in Schemes 1 and 2. Briefly, compound 7
was prepared by a selective Minisci acetylation22,23 of methyl
thiazole-5-carboxylate 6. Compound 8 was yielded by a condensa-
tion of 7 with N,N-dimethylformamide dimethyl acetal. Both com-
pounds 9 and 12 were readily produced using 8 as a key
intermediate under reported procedures.10,24 Finally, the designed
compounds 5a–5k and 5l were obtained by coupling 9 and 12 with
different amines 19 (Scheme 1), and followed by hydrogenation.
Similarly, the pyrrolopyridinyl thiazole amide derivative 5m
was synthesized14 using Pd-catalyzed Suzuki coupling reaction as
the key step (Scheme 2).
l
share significant sequence identity, they possess disparate func-
tions.1,2 Akt represents a key node in the PI3K-PKB-mTOR pathway
and is located at the crucial crossroads of various upstream signal-
ing events.3,4 Almost all the known oncogenic growth factors,
angiogenic factors, cytokines and steroid hormones regulate cell
growth and proliferation, cell survival protein synthesis, glucose
uptake and metabolism by activation of Akt.5 Deregulation of Akt
through mutation or amplification of upstream PI3K, loss of PTEN
function and activation of oncogenic receptor kinases results in
aberrant signaling.6–8 Constitutive activation and/or overexpres-
sion of Akt have been observed in a variety of human malignancies
and render cancer cells resistant to chemotherapy or molecular
target drugs.6 Therefore, Akt has been suggested as one of the most
attractive targets for new anticancer drug development. Several
classes of ATP-competitive or allosteric small molecular Akt
inhibitors9–18 have been discovered, among which GSK2141795
and MK-2206 have been recently approved by FDA for clinical
trials.19,20
l
As a part of our anticancer drug discovery program, a random
screening on a self-established focused library was performed to
search for new potential Akt inhibitors by a FRET-based Z’-Lyte
assay.21 Among all of the compounds tested, N-(1-amino-3-
phenylpropan-2-yl)-2-phenylthiazole-5-carboxamide (1) (Fig. 1)
The kinase inhibitory activities against Akts of compounds
5a–m were evaluated via a well established FRET-based Z’-Lyte
assay. Staurosporine (a pan-kinase inhibitor) was included as a
positive control to validate the screening assay. Under the screen-
ing conditions, staurosporine inhibited the kinase activities of
⇑
Corresponding author. Tel.: +86 20 32015276; fax: +86 20 32015299.
E-mail address: ding_ke@gibh.ac.cn (K. Ding).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.11.080

S. Chang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1208–1212
1209
O
NH2
S
N
N
H
1: Akt1 IC50 40,000 nM
HO
HO
O
O
NH2
NH2
S
S
N
N
N
N
H
H
2: Akt1 IC50 8,000 nM
3: Akt1 IC50 1,700 nM
HN
N
N
O
NH2
Cl
S
Cl
N
H
4: Akt1 IC50 6 nM
Akt2 IC50 23 nM
Akt3 IC50 3 nM
O
Ar
NH2
R2
S
*
N
N
H
5
Figure 1. 2-Substituted thiazole carboxamides as new Akt inhibitors.
Akt1, Akt2 and Akt3 with IC50 values of 0.12, 0.22 and 0.065
l
M,
important features of possible interactions could be derived from
the predicted binding mode of compound 5m. As shown in Fig. 2A,
the rigid pyrrolopyridine core was deeply buried in the ATP binding
pocket. It could form two essential hydrogen bonds with carbonyl
oxygen of Glu228 and nitrogen of Ala230 in the kinase hinge region
like other reported crystal structures of Akt inhibitors.14 The pyrrol-
opyridine core of compound 5m also occupied the hydrophobic re-
gion which was composed of residues Met227, Tyr229, Thr291,
Thr211, and Phe438. In addition, the 2,4-dichlorobenzyl stretched
out of the ATP binding pocket and could have an intense hydropho-
bic interaction with Phe161. Hence compounds with strong hydro-
phobic groups in R2 had notably better activity (Table 1). Thiazole
ring worked as a hydrophobic linker and the nitrogen atom of amide
attachedto thiazolecould interact withAsp292via a hydrogenbond.
Primary amine side chain might interact with Asp292, Asn279 and
Glu278 in the carbonyl-rich region via three pairs of hydrogen
bonds, which are same as the hydrogen bond interactions in the re-
ported X-ray complex structure of (2S)-2-(4-chlorobenzyl)-3-oxo-
3-[4-(7H-pyrrolo[2,3,d]pyrimidin-4-yl) piperazin-1-yl]propan-1-
amine and Akt1 kinase domain.17 Compared with compound 5m,
compound 5k (Fig. 2b) with a smaller amimopyrimidine core would
gain less hydrophobic interactions and van der Waals (VDW) con-
tacts, and the entropy will increase because of the additional degree
of freedom of the rotational bond in Ar group, which all probably
caused the decrease of activity. Similarly, pyrazol core in compound
5l was a much smaller group than amimopyrimidine and pyrrolo-
pyridine, which might be too short to form the two essential hydro-
gen bonds with the residues in the kinase hinge region.
respectively, which showed great consistency with the reported
data.10 As shown in Table 1, when the phenyl group in compound
1 was replaced by a 4-(2-N-methylamino) pyrimidinyl moiety, the
resulting compound 5a strongly inhibited the kinase activities of
Akt1, Akt2 and Akt3 with IC50 values of 0.18, 1.30 and 0.17 lM,
respectively. In addition, when the S-configuration in 5a was
switched to R-configuration (5b), about 6-10-time potency was
lost, which suggested that the stereochemistry of the compound
5a might be critical for its kinase inhibitory activity. Moreover,
the investigation also demonstrated that the replacement of the
benzyl group in 5a with a phenyl group caused a 3–4-fold decrease
of the Akt inhibitory activity (5c). Further structure–activity rela-
tionship studies showed that the substituted group on the benzyl
group in 5a had great impact on the kinase inhibitory activities.
For instance, when a 4-hydroxyl group was introduced (5g), the
potency was attenuated by about 50 times, while 2-chloro deriva-
tive (5i) was about 6- or 10-times more potent than the original
compound 5c. 4-Chloro substituted compound (5f) was also more
potent than 5c. Combinedly, 2,4-dichloro benzyl analogue 5k was
further designed and synthesized to display improved potency.
Taking compound 5k as a template, pyrazol thiazole amide 5l
and pyrrolopyridinyl thiazole amide 5m were designed and syn-
thesized by replacing 4-(2-N-methylamino) pyrimidine with small
pyrazole and rigid 7-azaindole rings. The results showed that com-
pound 5l was almost totally inactive against Akts, while the pyrro-
lopyridinyl thiazole derivative 5m displayed the best potencies
against 3 isoforms of Akt kinase.
In order to rationalize the affinity observed for our inhibitors, we
studied their binding modes within the ATP binding site of Akt1
(PDB: 3OCB) by using computational docking method. Several
Additionally, the kinase inhibitory activities of these new Akt
inhibitors were further validated by western blot analysis. The re-
sults were illustrated in Figure 3. It was clearly that compound 5m

1210
S. Chang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1208–1212
HN
N
HN
N
O
O
S
S
NH2
Cl
N3
i
N
N
HN
HN
Cl
Cl
h
Cl
HN
N
5l
13
O
S
N
OH
12
f, g
c
O
O
O
O
O
S
N
S
S
N
a
b
O
O
N
N
O
HN
6
7
8
N
N
O
S
HN
HN
N
O
H
d
9
N
N
N
N
O
O
S
S
e
NH2
n
N3
N
N
HN
HN
R1
n
R1
5a-5k
10
HO
HO
HO
O
l
j
k
R1
R1
R1
NHBoc
NH2
n
n
NH2
n
14
15
16
N3
N3
MsO
n
m
R1
R1
R1
NH2
n
NHBoc
n
NHBoc
n
17
18
19
Scheme 1. Reagents and conditions (n = 0 or 1): (a) 40% acetaldehyde, H2SO4, FeSO4–7H2O, t-BuOOH, 0 °C to rt, 73%; (b) DMF-DMA, toluene, reflux, 84%; (c) EtONa (2.1 equiv),
methyl guanidine hydrochloride (2.0 equiv), EtOH, 70 °C,16 h, 79%; (d) compound 19, EDC, HOBt, DIPEA, DMF, rt; (e) H2, Pd/C, MeOH, rt; or PPh3, THF/H2O; (f) hydrazine
hydrochloride, AcOH, reflux, 1 h, 77%; (g) NaOH, THF/H2O, rt; (h) EDC, HOBt, DIPEA, 19k, DMF, rt, 66%; (i) H2, Pd/C, MeOH, rt, 69%; (j) LiBH4, Me3SiCl, THF, rt; (k) (Boc)2O,
CHCl3, rt; (l) MsCl, Et3N, DCM, rt; (m) NaN3, DMF, 60 °C, 16 h; (n) 3 M HCl, MeOH, 60 °C, overnight, quant.
Br
O
O
PhO2S
O
N
B
N
a
b,c
d
e,f
S
N
O
H
N
H
N
H
N
N
N
N
O
N
SO2Ph
N
SO2Ph
20
21
22
23
24
PhO2S
N
N
HN
g
h,i
N
O
S
O
N3
Cl
S
NH2
N
HN
Cl
N
HN
Cl
25
5m
Cl
Scheme 2. Reagents and conditions: (a) MCPBA, DME, 48%; (b) (CH3SO2)2O, (CH3)4NBr, DMF, 56%; (c) PhSO2Cl, NaH, DMF, 72%; (d) Pd(dppf)2Cl2, bis(pinacolato)diboron,
KOAc, DMF, 80 °C, 67%; (e) Pd(PPh3)4, K2CO3, ethyl 2-bromothiazole-5-carboxylate, DMF, 80 °C, 48%; (f) LiOH, THF/H2O, rt; (g) EDC, HOBt, DIPEA, 19k, DMF, rt, 85%; (h) NaOH,
THF/H2O, rt; (i) H2, Pd/C, MeOH, rt, 78%.

S. Chang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1208–1212
1211
Table 1
Structure–activity relationship of 2-substituted thiazole carboxamide derivatives as new potent Akt inhibitorsa
O
Ar
S
R2
∗
N
HN
NH2
HN
HN
HN
N
N
N
B =
A =
C =
N
;
;
*
*
*
Compd
R2
Ar
R/S
Kinase inhibition IC50
Akt2
(l
M)
Cell growth inhibition IC50
PC3
(
l
M)
Akt1
Akt3
LnCaP
Du145
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
STSP
Benzyl
Benzyl
Phenyl
A
A
A
A
A
A
A
A
A
A
A
B
C
S
R
S
S
S
S
S
S
S
S
S
S
S
0.18
1.85
0.55
0.58
1.39
0.15
10.9
0.74
0.033
4.00
0.15
>50
1.30
8.42
4.69
5.70
7.32
6.24
20.5
21.8
1.95
>50
0.17
1.06
0.50
1.36
13.9
2.32
7.16
8.13
0.89
24.8
5.05
0.26
1.75
0.70
11.93
0.23
NT
7.50
31.0
8.32
14.9
46.0
7.45
49.2
20.5
6.72
2.66
8.06
10.99
0.90
NT
2.54
14.1
2.89
6.63
15.0
7.54
9.59
12.6
10.1
2.66
4.09
12.1
2.84
NT
4-Me-benzyl
4-MeO-benzyl
4-Cl-benzyl
4-OH-benzyl
4-NO2-benzyl
2-Cl-benzyl
4-Ph-benzyl
2,4-Dichlorobenzyl
2,4-Dichlorobenzyl
2,4-Dichlorobenzyl
0.52
0.63
0.11
10.86
0.34
0.083
5.47
0.074
>50
0.90
>50
0.20
0.215
0.025
0.122
0.024
0.065
a
Akt activity assays were performed using the FRET-based Z’-Lyte assay according to the manufacturer’s instructions. The antiproliferative activities of the compounds
were evaluated using MTT assay. The data were means from at least 3 independent experiments. STSP: Staurosporine, NT, not tested.
Figure 2. (A) Predicted binding mode of compound 5m at the ATP binding site of Akt1. (B) Predicted binding mode of compound 5k at the ATP binding site of Akt1. The
coloring is described as follows: Green, Akt1 kinase domain; Cyan, compound 5m; Purple, compound 5k; Orange, hinge region of Akt1 kinase domain; Red, oxygen atom, Blue,
nitrogen atom; Yellow, sulfur atom; Light green, chlorine atom. The hydrogen bonds are denoted with blue dashed lines. All structure figures were prepared using PyMol 0.99
(http://pymol.sourceforge.net/).
barely affected the protein level of phosphorylated Akt, but dose-
dependently inhibited the phosphorylation of MDM2 and GSK3b,
which were both Akt downstream phosphorylating substrates,25
after four-hour treatment. The results were highly consistent with
the observation on many other selective Akt inhibitors.29,30
The in vitro anti-tumor activities of the designed compounds
were also evaluated by MTT assay in three prostate cancer cell lines
(LnCap, PC3 and Du145) with different p53 status (Table 1).26,27
Corresponding to their potent Akt kinase inhibitory activities, the
compounds strongly suppressed the growth of three different types
of human prostate cancer cells. The most potent compound 5m
inhibited the growth of LnCap, PC3 and Du145 with IC50 values of
pAKT
β
pGSK3
pMDM2
GAPDH
0.23, 0.90 and 2.84 lM, respectively. Further data analysis sug-
gested that almost all the new Akt inhibitors preferred to inhibit
the growth of LnCap cells which possess wild-type p53. However,
significantly lower potencies were observed for PC3 and Du145
cancer cells which lack p53 or bear mutated form of p53. The selec-
tivity on LnCap cells might be due to the consequent inhibitory
activity against MDM2 imposed by Akt inhibitors, which could
potentate the tumor suppression of p53 subsequently.28
DMSO 0.1 0.2 0.5 1.0 2.0 5.0 10 µM
Figure 3. Compound 5m dose-dependently inhibits the phosphorylation of MDM2
and GSK3b in LnCap cells (four-hour treatment). Results are representative of at
least 3 independent experiments.

1212
S. Chang et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1208–1212
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In summary, a new series of 2-substituted thiazole carboxam-
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ides were initially identified as potent pan inhibitors against all
three isoforms of Akt (Akt1, Akt2 and Akt3). As one of the most po-
tent compounds, 5m inhibited the kinase activities of Akt1, Akt2
and Akt3 with IC50 values of 25, 196 and 24 nM, respectively. The
Akt inhibition of compound 5m was further validated using cell ly-
sate assays. Furthermore, the compounds also potently inhibited
the cell growth of three different types of human prostate cancer
cells. Theses inhibitors may be taken as new potential lead com-
pounds for further development of novel anticancer agents.
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Acknowledgments
15. McHardy, T.; Caldwell, J. J.; Cheung, K. M.; Hunter, L. J.; Taylor, K.; Rowlands,
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We thank the National High Technology Research and Develop-
ment Program (2010CB529706, 2009CB940904), National Natural
Science Foundation(21072192), 100-Talent Program of the Chinese
Academy of Sciences (CAS) and National Nature Science Founda-
tion of China (81001446) for their financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.11.080.
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