Indolinone based phosphoinositide-dependent kinase-1 (PDK1) inhibitors. Part 1: Design, synthesis and biological activity

Article abstract of DOI:10.1016/j.bmcl.2007.04.071

HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.

Full text of DOI:10.1016/j.bmcl.2007.04.071

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3814–3818
Indolinone based phosphoinositide-dependent kinase-1
(PDK1) inhibitors. Part 1: Design, synthesis and biological activity
Imadul Islam, Judi Bryant, Yuo-Ling Chou, Monica J. Kochanny, Wheeseong Lee,
Gary B. Phillips, Hongyi Yu, Marc Adler, Marc Whitlow, Elena Ho, Dao Lentz,
Mark A. Polokoff, Babu Subramanyam, James M. Wu, Daguang Zhu,
Richard I. Feldman and Damian O. Arnaiz*
Berlex Biosciences, 2600 Hilltop Dr. Richmond, CA 94804, USA
Received 8 March 2007; revised 20 April 2007; accepted 23 April 2007
Available online 27 April 2007
Abstract—HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517)
which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Ó 2007 Elsevier Ltd. All rights reserved.
Protein kinases are critical regulators of cellular pro-
cesses in normal tissues and disease. A number of small
molecule kinase inhibitors such as Iressa, Gleevec, and
Sorafenib have been approved for the treatment of can-
cer. Compounds targeting other kinases are in develop-
ment.1 One promising protein kinase target for the
development of new cancer drugs is phosphoinositide-
dependent kinase-1 (PDK1). PDK1 is required for the
activation of Akt, which plays a key role in processes
such as tumor cell growth, protection from apoptosis,
stimulation of epithelial to mesenchymal transition
(EMT), and tumor angiogenesis.2 The Akt family of
Ser/Thr protein kinases is comprised of three highly
homologous members (AKT1, AKT2, and AKT3), all
of which require PDK1 for activation. PDK1 activates
Akt by phosphorylating its activation loop (e.g., on res-
idue Thr 308 of AKT1), which initiates a conforma-
tional change to the active protein.3
brane through interaction with their pleckstrin homology
domains.4 PI3K and Akt activity become highly elevated
in many tumors through the up-regulation or mutation of
upstream signaling molecules such as EGF receptors,
Ras, Src, and c-ABL, or by over-expression of PI3K
itself.2a–c Loss of the tumor suppressor PTEN/MMAC1,
which negatively regulates PI3K activity, is also a
common mechanism of Akt activation in tumor cells.5
In addition to Akt, PDK1 has been shown to be a crit-
ical activator of other kinases in the AGC kinase super-
family that are important promoters of cancer
progression, including protein kinase C (PKC), serum
and glucocorticoid-regulated kinase (SGK), and p70
ribosomal S6 kinase (S6K1).2 These kinases have a
homologous region in their activation loops containing
a consensus substrate recognition site for PDK1.6
The role of PDK1 in several distinct signaling pathways
that are important for tumor progression provides fur-
ther rationale for the development of small molecule
PDK1 inhibitors as anticancer drugs. Previously, we
reported on the discovery and characterization of
aminopyrimidines with potent inhibitory activity against
PDK1.7 Several additional reports of small molecule
Akt inhibitors have also appeared in the literature.8
Numerous studies demonstrate that Akt is highly acti-
vated in many common tumor types, including melanoma
and breast, lung, gastric, prostate, hematological, and
ovarian cancers. Activation of Akt by PDK1 is promoted
by phosphoinositide 3-kinase (PI3K) activity in cells,
resulting in the production of PtdIns-3,4-P2 or PtdIns-
3,4,5-P3 that recruit Akt and PDK1 to the plasma mem-
High-throughput screening using a PDK1 mediated
AKT2 activation assay (cAKT29) identified 1 as a
1.8 lM inhibitor (Fig. 1). This assay can identify inhib-
itors of Akt activation as well as inhibitors of AKT2 or
Keywords: Ser/Thr kinases; PDK1; Akt; PI3-kinase; Cancer.
*
Corresponding author. Tel.: +1 510 734 0683; e-mail: damian_
arnaiz@yahoo.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.04.071

I. Islam et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3814–3818
3815
Table 2. PDK1 activity of methyl analogs on the pyrrole ring and
alkene
N
H
3'
O
R
5'
Alk
N
H
N
HO
H
1
O
IC50 cAKT = 2.3 μM
IC50 PDK1 = 0.52 μM
IC50 P-AKT PC-3 ~ 32 μM
IC50 PKA = 16 μM
N
H
a
cAKT2 IC50 (nM)
Compound
Alk
R
1e
2a
2b
2c
2d
2e
2f
H
H
H
30-Me
40-Me
50-Me
50-Et
340
80
Figure 1. Biological activity of 1.
Me
H
280
280
680
2300
1100
PDK1 activity. Further testing determined that 1 blocks
PDK1 kinase activity10 and inhibits the activation of
Akt in tumor cells in vitro.7,11 Compound 1 was previ-
ously reported to be an inhibitor of VEGF receptors,12
CDK4,13 and other kinases.14 We found that 1 also
inhibits PKA although with 9-fold less potency. Due
to the close homology of PKA with PDK1, PKA was
used as an initial measure of kinase selectivity. The goal
was to achieve 50-fold selectivity or higher. Herein we
disclose the optimization of 1, leading to 4i (BX-517),
a potent and selective inhibitor of PDK1.15
H
H
H
H
30,50-Me
a Values are means of multiple experiments (n P 2), standard deviation
is <30% of the mean.
Table 3. PDK1 activity of analogs substituted at the 5-position of the
indolinone ring
N
5
R
H
The compounds in Tables 1–4 were synthesized by con-
densation of indolinones 5 and pyrroles 6 as shown in
Scheme 1 affording exclusively the Z-isomer as shown.12
The reaction with aldehydes was facile; however, the
reaction with ketones required more drastic conditions.
Indolinones 5 and pyrroles 6 are commercially available
or were prepared according to the literature.16
O
N
H
a
cAKT2 IC50 (nM)
Compound
R
1e
3a
3b
3c
3d
3e
3f
OH
OMe
340
580
290
670
260
120
200
580
990
1000
530
55
SO2NH2
CO2Me
CO2H
CONH2
The cyano (3h) and nitro (7) analogs were further elab-
orated as shown in Scheme 2. The cyano analog was
converted to the tetrazole (3f) analog under standard
reaction conditions. The amino analog (8) was reacted
with methanesulfonyl chloride to afford sulfonamide 3j
or with trimethylsilyl isocyanate to afford the urea ana-
logs (3l, 4i–l).
5-Tetrazole
NH2
CN
3g
3h
3i
CH2NH2
NHSO2Me
NHCOMe
NHCONH2
3j
3k
3l
18
To guide the optimization, a model of 1 bound to PDK1
was built. The model was based on an X-ray structure of
a Values are means of multiple experiments (n P 2), standard deviation
is <30% of the mean.
Table 1. PDK1 activity of methyl and hydroxyl analogs on the
indolinone ring
1 bound to a related Ser/Thr kinase. The model predicts
that the indolinone amide and pyrrole interact with the
hinge region of PDK1 similar to the binding conforma-
tion of other indolinone based inhibitors bound to other
kinases.17 Based on the predicted binding conformation,
substitution on the 7-position of the indolinone or the
50-position of the pyrrole should be disfavored for steric
reasons. Substitution on the 5- or 6-position of the ind-
olinone could lead to interaction with Lys 111 and/or
Thr 222. Substitution on the 4-position of the indoli-
none, the alkene, or the 30- or 40-position of the pyrrole
could lead to interaction with Glu 166.
4
N
H
R
O
N
H
7
a
cAKT2 IC50 (nM)
Compound
R
1
H
1800
510
1a
1b
1c
1d
1e
1f
1g
4-Me
5-Me
7-Me
4-OH
5-OH
6-OH
7-OH
2700
>26,000
1000
340
Initially, methyl and hydroxyl groups were placed on
different positions of 1 to identify sites amenable to sub-
stitution. The results for the indolinone ring are shown
in Table 1. Substitution at the 7-position was not toler-
ated (1c and 1g). Methyl substitution on the 4-position
900
>26,000
a Values are means of multiple experiments (n P 2), standard deviation
is <30% of the mean.

3816
I. Islam et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3814–3818
(2b and 2c). Methyl substitution on the 50-position re-
Table 4. PDK1 activity of alkene analogs
duced potency somewhat; however, ethyl substitution
or 30, 50-dimethyl substitution reduced potency more
significantly (2d–f).
Alk
N
R
H
O
N
H
Based on the model of 1 bound to PDK1 the 5-hydroxyl
group of 2a could interact with Lys 111 and/or Thr 222.
In order to optimize this interaction, a series of inhibi-
tors with varied substitution at the 5-position were pre-
pared. The results are shown in Table 3.
a
cAKT2 IC50 (nM)
Compound
R
Alk
3b
4a
4b
4c
4d
4e
4f
SO2NH2
SO2NH2
H
Me
290
67
SO2NH2
SO2NH2
Et
Ph
14
29
Three analogs were more potent than 1e. The amide (3e)
was 3-fold more potent, the acetamide (3k) 6-fold, and
the urea (3l) 19-fold. The amide, acetamide, and urea
analogs have a carbonyl that can interact with the side-
chains of Lys 111 and Thr 222. Based on the relative po-
tency of these three analogs, it appears that the optimal
position of the carbonyl is on the second atom from the
indolinone core. With the exception of the cyano (3h)
and aminomethyl (3i) analogs, the remaining analogs
were equipotent with 1e. The binding pocket for the sub-
stituents on the 5-position appears to be highly accom-
modating since none of the analogs is more than 3-
fold less potent than 1e. This is not surprising since
the indolinone inhibitors bind into the same channel
as ATP. Substituents on the 5-position of the indolinone
should roughly occupy the same space as the phosphate
tail of ATP.17
SO2NH2
SO2NH2
CO2Et
CO2H
CONH2
34
4200
3900
6100
5400
18
SO2NH2
SO2NH2
SO2NH2
4g
4h
3l
CONHEt
CONEt2
H
NHCONH2
NHCONH2
NHCONH2
NHCONH2
NHCONH2
4i
Me
Et
5
4j
3
4k
4l
Ph-3–NH2
4-Pyridine
9
10
a Values are means of multiple experiments (n P 2), standard deviation
is <30% of the mean.
improved potency ca. 4-fold (1a). Hydroxyl substitution
on the 5-position improved potency 5-fold while substi-
tution on the 6-position had little effect (1e and 1f).
These data support the predictions based on the model.
The results for the alkene and pyrrole ring are shown in
Table 2. In this case, the study was conducted on the
more potent 5-hydroxy analog 1e. Methyl substitution
on the alkene improved potency 4-fold (2a vs 1e). Sub-
stitution on the pyrrole 30- or 40-position was tolerated
Several analogs with either sulfonamide or urea on the
5-position of the indolinone ring were prepared investi-
gating substitution on the alkene. The results are shown
in Table 4. In the sulfonamide series, methyl substitution
improved potency 4-fold (4a vs 3b).
R3
R2
R3
N
a or b
H
R1
R2
O
R1
+
O
N
H
N
N
H
O
H
5
6
1-4
Scheme 1. Synthesis of indolinones 1–4. Reagents and conditions: (a) pyrrolidine, EtOH, 60 °C (11–68%); (b) cat. piperidine, 130 °C (3–45%).
A
N
N
N
N
N
NC
H
H
a
N
H
O
O
N
H
N
H
3f
3h
R2
R2
R2
B
N
H
N
N
H2N
O2N
H
N
H
c or d
H
b
R1
O
O
O
N
H
N
H
N
H
8
7
9
Scheme 2. Elaboration of cyano and nitro analogs. Reagents and condition: (a) Bu3SnCl, NaN3, toluene, reflux (25%); (b) Pd/C, MeOH, H2 (40 PSI,
85%); (c) MeSO2Cl, satd NaHCO3, THF (7%); (d) TMSN@C@O, THF (89%).

I. Islam et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3814–3818
3817
Table 5. Properties of 4i
of the close homology of PKA with PDK1, we hypothe-
sized that a compound with high selectivity against PKA
would also have high selectivity against other kinases.
This was borne out by further profiling. 4i was 100-fold
selective or better against a panel of seven additional
Ser/Thr and Tyr kinases.19 Not all properties of 4i were
optimal. 4i has poor solubility in aqueous media and has
a poor ADME profile.
Me
H
N
H2N
N
H
O
O
N
H
4i
Assays
IC50 (nM)
ADME
cAKT28
PDK19
5a
Sol. PBSc 2 mg/L
An X-ray structure of 4i and PDK1 is shown in Figure
2. The binding conformation of 4i is similar to that pre-
dicted by the model. The indolinone core occupies the
same site as the adenosine of ATP and the inhibitor
makes three critical H-bonds to the backbone of the
hinge region. The nitrogen of the indolinone interacts
6a
t1/2 24 min
Cld 31 mL/min/kg
%Fe <1%
d
P-AKT PC-310
PKAa
100–1000b
1600
a Values are means of multiple experiments (n P 2), standard deviation
is <30% of the mean.
b Determined from 10 experiments.
c Determined from 1 experiment.
with the carbonyl of Ser 160 (2.9 A), the carbonyl inter-
˚
acts with the amide of Ala 162 (2.8 A) and the pyrrole
˚
d Dosed 2 mg/kg iv in three rats.
nitrogen interacts with the carbonyl of Ala 162
˚
e Dosed 10 mg/kg po in three rats.
(2.9 A). The 5-urea group interacts with Lys 111
˚
˚
(3.2 A) and Thr 222 (2.8 A). A superposition of 2a and
4i is shown in Figure 3. The 5-hydroxyl group of 2a
forms a water mediated H-bond with the side chains
of Lys 111 and Thr 222, whereas the urea group of 4i
interacts with these two residues directly explaining the
greater potency of 4i. In addition, the interaction
Ethyl was 4-fold more potent than methyl (4b vs 4a),
while phenyl (4c) and carboethoxy (4d) showed no
improvement over methyl. The acid (4e) and the amide
(4f–h) analogs were much less potent. Modeling suggests
that the poor potency of the acid analog (4e) may be due
to a negative interaction with Glu 166. For the amide
analogs (4f–h), the poor potency may be due to steric
interactions between the substituents on the amide and
the 4-proton of the indolinone and the 30-proton of
the pyrrole. In the urea series, methyl substitution im-
proved potency 4-fold affording single-digit nanomolar
activity (4i vs 3l). Unlike the sulfonamide series, ethyl
(4j) did not improve potency further. Aniline (4k) and
pyridyl (4l) analogs also did not improve potency.
Based on potency and ease of synthesis 4i18 was se-
lected for further evaluation (Table 5). 4i had similar
activity in the PDK1 assay and in the PDK1 mediated
AKT2 activation assay (cAKT2) supporting that these
indolinone inhibitors blocked Akt activity by inhibiting
PDK1. Additionally, 4i blocked AKT2 activation in
cells with submicromolar potency. The PKA selectivity
was 320-fold, exceeding the goal of the project. Because
Figure 3. 4i (green carbon atoms) superimposed on the X-ray structure
of 2a (orange) bound to PDK1, PDB entry 2PE0. The pink lines show
the water mediated H-bonds formed by the 5-OH group on 2a to the
side chains of Lys 111 and Thr 222. The figure also shows the H-bonds
to the hinge residues, Ser 160 and Ala 162.
Figure 2. Divergent stereo view of the X-ray structure of 4i bound to PDK1, PDB entry 2PE1. The three H-bonds from the inhibitor to Ser 160 and
Ala 162 are typical for indolinone based kinase inhibitors. The urea accepts an H-bond from the side chain of Lys 111 and Thr 222 conferring
selectivity for PDK1.

3818
I. Islam et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3814–3818
Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J. R.;
Huber, H. E.; Duggan, M. E. Bioorg. Med. Chem. Lett.
2005, 15, 761; (e) Zhao, Z.; Leister, W. H.; Robinson, R.
G.; Barnett, S. F.; Defeo-Jones, D.; Jones, R. E.; Hart-
man, G. D.; Huff, J. R.; Huber, H. E.; Duggan, M. E.;
Lindsley, C. W. Bioorg. Med. Chem. Lett. 2005, 15, 905.
9. cAKT2 (33P-SPA): The coupled assay can detect inhib-
itors of AKT2 activation, as well as direct inhibitors of
PDK1 or AKT2. Inactive AKT2 is activated in situ by
incubating with PDK1 and PtdIns-3,4-P2 in the presence
of compound, 33P-ATP, and a biotinylated peptide sub-
strate for AKT2. The peptide is captured on streptavidin-
coated SPA beads for detection.
between the 5-urea group of 4i and Thr 222 may explain
the selectivity shown by 4i. Other kinases have a differ-
ent amino acid in place of Thr. However, PKA also
has a Thr residue suggesting a different mechanism of
selectivity. Preliminary modeling studies indicate that
the reduced affinity of 4i in PKA may stem from steric
factors. The gatekeeper residue in PKA is Met 120. This
bulky residue points downward from the hinge region
into the adenosine binding site and may preclude bind-
ing of 4i. On the other hand, PDK1 has Leu 159 in
the gatekeeper position. This shorter residue may pro-
vide enough room to accommodate the urea group from
our inhibitors.
10. PDK1 (33P-filter paper): PDK1 inhibitory activity is
measured directly using PDK1, a peptide substrate, 33P-
ATP, and compound followed by capture on P81
phospho-cellulose paper and detection by phorphor-
imaging.
In summary, starting from 1, a non-selective kinase
inhibitor with moderate activity against PDK1, we de-
signed and synthesized 4i, a potent and selective inhibi-
tor of PDK1. Key steps of the optimization were the
addition of a urea group to the 5-position of the indoli-
none which improved activity 100-fold, and of a methyl
group to the alkene which improved activity 4-fold fur-
ther. Because of the close homology of PKA and PDK1,
we did not expect to find selectivity for PKA. However,
4i was highly selective against PKA although the reason
for this selectivity is still not clearly understood. Further
optimization based on 4i will be described in the follow-
ing paper.
11. P-AKT in PC-3 cells: Inhibition of Akt phosphorylation in
cells is measured by incubating compounds with cells,
followed by lysis and standard immunoblotting techniques
using phosphospecific antibodies to Akt P-Thr 308.
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15. Previously disclosed as a poster: Feldman, R. I.; Bryant,
J.; Chou, Y.-L.; Islam, I.; Kochanny, M. J.; Lee, W.;
Phillips, G. B.; Yu, H.; Adler, M.; Whitlow, M.; Ho, E.;
Lentz, D.; Polokoff, M. A.; Subramanyam, B.; Wu, J. M.;
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19. Unpublished data.