Discovery of pyrrolopyrimidine inhibitors of Akt

Article abstract of DOI:10.1016/j.bmcl.2010.08.053

The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.

Full text of DOI:10.1016/j.bmcl.2010.08.053

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5607–5612
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of pyrrolopyrimidine inhibitors of Akt
James F. Blake a, , Nicholas C. Kallan a, Dengming Xiao a, Rui Xu a, Josef R. Bencsik a, Nicholas J. Skelton b,
⇑
Keith L. Spencer a, Ian S. Mitchell a, Richard D. Woessner a, Susan L. Gloor a, Tyler Risom a, Stefan D. Gross a,
Matthew Martinson a, Tony H. Morales a, Guy P. A. Vigers a, Barbara J. Brandhuber a
a Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA
b Genentech Inc., 1 DNA Way, South San Francisco, CA 94080-4990, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhib-
itors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent
inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor
xenografts.
Received 30 June 2010
Revised 9 August 2010
Accepted 11 August 2010
Available online 13 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keyword:
Akt kinase inhibitors
Protein kinase B (Pkb/Akt) is a serine–threonine kinase and
downstream target for phosphatidylinositol 3-kinase (PI3K) that
plays a central role in the regulation of cell survival and prolifera-
tion.1 Constitutive activation and overexpression of Akt has been
identified in a wide variety of human tumors, including breast,
prostate, and ovarian carcinomas.2 Additionally, loss of PTEN
activity in a large number of tumors further contributes to the
attractiveness of inhibiting Akt activity as a novel therapeutic
approach to cancer treatment.3 Akt comprises three isoforms
(Akt1, Akt2, and Akt3) that share significant sequence identity
while possessing disparate functions.4 Knockout data using Akt
shRNA suggests that maximum efficacy in tumor-bearing nude
mice would be achieved by inhibiting all three isoforms.5
Docking of compounds 2 and 3 suggested that the former could
more easily form better interactions with Glu236, Glu279, and the
hydrophobic residues present in the P-loop (Fig. 2).8 In this model
the quinazoline ring occupies the hydrophobic cavity near the
hinge region and accepts a hydrogen bond from the backbone
NH of Ala232. Based on the docked structure of 2, we prepared a
series of substituted benzyl analogs to probe the SAR of the nascent
hit (Table 1). Small hydrophobic substitution proved to afford the
largest potency increases. Replacement of the phenyl ring with
1-napthyl (15) resulted in significantly lower potency versus
Akt1 (3.2
l
M), as did the incorporation of 2- (20) or 3-pyridyl
M and 7.1 M, respectively. Neither the secondary
(22, 3.2 lM), nor tertiary amine (23, 7.7 lM) of 2, proved to be po-
(21), 43.1
l
l
We describe the discovery and optimization of a series of pan
Akt inhibitors that were discovered via combinatorial library syn-
thesis, high throughput screening (HTS), and structure based drug
design. Originally, compound 1 (Fig. 1) was synthesized as part of a
combinatorial library that targeted the ATP cleft of kinases. HTS
tent inhibitors of Akt1, presumably owing to loss of interaction
with the two glutamate residues. From this evaluation, 4 emerged
as our initial lead for further optimization efforts.
In vitro cellular potency of 4 was assessed by measurement of
phospho-PRAS40 levels in the LNCaP cell line (cell IC50 = 1.5 l
M).9
screening identified 1 as a hit against Akt1 with an IC50 = 2.1
l
M.6
Additionally, 4 was shown to possess excellent aqueous solubility
Synthesis of the individual enantiomers with (R)-(2), and (S)-ste-
of 3.6 mg/mL (at pH 7.4 via shake flask method).
reochemistry (3) showed a marked difference in potency with
Akt1 IC50s of 884 nM and >85 lM, respectively.
Initial SAR around the quinazoline ring probed for possible posi-
tions that would allow for additional diversification (Table 2).
While no X-ray structures of Akt1 were available at the outset of
our efforts, several X-ray structures of Akt2 and PKA kinases were
known.7 Given the high identity among the kinase domains of
Akt1/2/3, use of the X-ray structure of Akt2 for our early optimiza-
tion efforts was a viable strategy.
O
N
N
N
N
NH2
1
⇑
Corresponding author. Tel.: +1 303 386 1262.
E-mail address: jblake@arraybiopharma.com (J.F. Blake).
Figure 1. Combinatorial library HTS hit.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.08.053

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J. F. Blake et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5607–5612
Table 2
Quinazoline ring SAR
Cl
O
N
N
N
N
NH2
R1
R3
R2
Compound R1
R2
R3
Akt1 inhibition IC50a (nM)
24
25
26
27
28
29
30
31
32
33
H
H
CH3
H
H
H
H
H
H
H
H
H
CH3
4-Pyrazole
NH2
NHCH3
N(CH3)2
N-Acetamide
N-
CH3 3203 1348
F
30 12
100 59
54 21
H
H
H
H
H
H
H
H
80 43
43 22
98 19
536 201
868 438
174 72
Figure 2. Compound 2 docked into the X-ray structure of Akt2 (PDB code: 1O6K).
H
Methylsulfonamide
Phenyl
t-Butyl
34
35
H
H
H
H
809 215
1460 775
a
Table 1
Akt kinase inhibition
Values are means of three or more experiments, standard deviation is given.
R
O
N
The influence of amine chain length on potency was probed.
b-amino amides (50–53) were nearly as potent as the shorter
-amino amides. Moreover, the longer b-amino amide side chain
N
N
N
a
NH2
afforded the possibility of maintaining the same overall relation-
ship between the aromatic ring and amine position via deletion
of the methylene linker of the former. Thus, the 4-Cl phenyl b-ami-
no acid, coupled with the pyrrolopyrimidine core proved to be
quite potent (e.g., 56, Table 4). As in the quinazoline series, the
amine (S)-stereoisomer proved much less potent (57). In general,
Compound
R
Akt1
Akt2 inhibition
IC50 (nM)
Akt3
a
inhibition
inhibition
a
a
IC50 (nM)
IC50 (nM)
2
4
5
6
7
H
4-Cl
4-CN
4-F
4-OCH3
4-CH3
4-Br
2-Cl
3-Cl
2-,4-diCl
3-,4-diCl
3-,4-diF
4-CF3
4-Phenyl
3-,5-diF
3-,4-
884 238
20
284 112
118 20
150 40
74 34
8362 5146
118 47
4371 2649
1288 431
1485 569
630 159
8410 1354
179 29
2718 334
1122 275
2056 398
754 84
6
we found that primary
a-amino amides tended to have cellular
potency similar to the b-amino amides (e.g., 46 and 56, cell
IC50 = 38 nM and 138 nM, respectively). For all of these analogs,
the Akt2 and Akt3 potencies followed the same trends albeit with
potencies ca. 5–10 fold lower than versus Akt1.
Access to the 5-methyl pyrrolopyrimidines originated from
readily available pyrrolopyrimidine 62 as shown in Scheme 1.
Treatment of 62 with N-bromosuccinimide gave clean bromina-
tion at the 5-position. Subsequent nitrogen protection as the
phenyl sulfonamide and incorporation of the Boc protected
piperazine via SNAr gave 63 in good overall yield. Conversion
of the bromide to the methyl was smoothly mediated under
Pd catalyzed conditions, which following acid promoted Boc
deprotection, afforded 64 as the di-HCl salt. Synthesis of the
8
9
30
5
279 60
363 92
10
11
12
13
14
16
17
18
19
2346 1040
595 238
142 36
51 17
81
95 34
2883 781
690 263
838 428
26,500 9339
5586 2345
1067 359
433 85
872 305
707 178
37,826 13,890 13,916 1527
5027 1389
4951 1362
25,110 4174
6079 1589
1464 62
485 63
666 33
746 65
7
6073 1262
5769 739
OCH3
a
Values are means of three or more experiments, standard deviation is given.
pool of (R)
a-amino acids used to prepare compounds 2–45
was achieved using a chiral hydrogenation route as outlined in
Although several of the quinazoline ring substitutions were toler-
ated, none improved the potency, which led us to explore alternate
hinge binding cores while maintaining the 4-Cl benzyl amino acid
of 4.
A number of the quinazoline replacements showed excellent
potency (Table 3), and introduction of a hydrogen bond donor for
interaction with the carbonyl of Glu228 at the hinge resulted in a
significant potency boost (e.g., 40 and 44).
Substitution of methyl at C5 (46) on the pyrrolopyrimidine core
resulted in a substantial boost in Akt1 potency, with an IC50 of ca.
1 nM (Table 4). Subsequent substitution of ethyl (47), cyclopropyl
(48), and Cl (49) produced compounds with similar levels of po-
tency relative to the methyl substituted core. Methyl substitution
at C6 led to decreased potency (Akt1 IC50 = 52 nM; 60) as did the
5-,6-dimethyl analog (Akt1 IC50 = 21 nM; 61).
Scheme 2.
Formation of the key amino acrylate by treatment of the appro-
priate aldehyde under Horner–Wadsworth–Emmons conditions
led exclusively to the Z regioisomer 65 in good yield. Asymmetric
reduction using catalytic Rh-(R,R)-DuPhos under 40 psi hydrogen,
followed by subsequent ester hydrolysis provided the desired (R)
a
-amino acid in excellent yield and >95% ee, as determined by chi-
ral HPLC.
The b-amino acids originated from readily available phenyl
acetate esters (Scheme 3). Hydroxymethylation of the ester by
treatment with paraformaldehyde and NaOMe, followed by activa-
tion to the mesylate and concomitant b-elimination gave acrylate
66.
Introduction of the amine by Michael addition followed by
successive amine protection as the t-butyl carbamate and ester

J. F. Blake et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5607–5612
5609
Table 3
Alternative hinge binding motifs
Cl
O
N
N R
NH2
a
a
Compound
R
Akt1 inhibition IC50 (nM)
Compound
R
Akt1 inhibition IC50 (nM)
N
N
36
46 11
21,233 9368
3321 337
41
8122 1410
N
N
N
37
38
42
43
22,920 7402
2048 851
N
N
H
N
N
N
N
N
N
H
N
N
N
39
40
114 83
44
45
5
2
N
H
N
N
8
4
N
104 33
N
N
H
N
N
H
a
Values are means of three or more experiments, standard deviation is given.
Table 4
Pyrrolopyrimidine SAR
O
N
N
N
N
R1
R2
NH
R3
a
Compound
R1
R2
R3
CH3
Ethyl
cycloPr
Cl
H
CH3
H
Akt1 inhibition IC50 (nM)
46
47
NH2
NH2
NH2
NH2
CH2NH2
CH2NH2
CH2NHCH3
CH2N(CH3)2
NH2
1
2
0
1
Cl
48
49
50
51
52
53
54
55
56
57
58
59
2
1
5
2
18
1
0
2
0
5
H
88 23
4-F benzyl
2-(2,3)Dihydroindene
4-Cl phenyl
CH3
CH3
H
H
Cl
3
30
2
2
7
1
NH2
CH2NH2
(S)-CH2NH2
CH2NH2
CH2NH2
63 32
3-,4-diCl phenyl
4-iPr benzyl
2
0
H
604 319
a
Values are means of three or more experiments, standard deviation is given.
hydrolysis gave the racemic b-amino acid 67 in excellent overall
yield. The chiral amino acid was obtained from separation of the
racemate via SFC. With the requisite amino acid and core in hand,
coupling was carried out using the conditions illustrated in Scheme
4. Treatment of the amine 68 with Hünig’s base, HBTU and the
appropriate amino acid gave 69 in excellent yield. Subsequent
hydrolysis of the phenyl sulfonamide and Boc deprotection affor-
ded the desired compound 70 as the bis HCl salt.
During our lead optimization efforts we were able to obtain an
X-ray structure of 50 bound to Akt1. The crystal structure con-
firmed that the pyrrolopyrimidine core interacts via a pair of H-
bonds to the hinge region of Akt1 at Ala230 and Glu228 (Fig. 3).
The longer amine side chain interacts in the carbonyl-rich region
with the carboxylate side chain of Glu234 (3.3 Å) and the backbone
carbonyl of Glu278 (2.9 Å). The side chain carbonyl oxygen of
Asn279 is ca. 3.8 Å from the amine nitrogen, and the carboxylate

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J. F. Blake et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5607–5612
H
N
Boc
N
Cl
N
N
N
N
Br
N
N
a-c
N
d-e
2HCl
N
H
N
N
N
PhO2S
PhO2S
62
64
63
Scheme 1. Reagents and conditions: (a) NBS, CDCl3, reflux, 79%; (b) NaH, PhSO2Cl, DMF, 100%; (c) t-butyl piperazine-1-carboxylate, Et3N, NMP, 100 °C, 86%; (d) Me2ZnCl,
Pd(PPh3)4, THF, reflux, 94%; (e) 4 N HCl–dioxane, DCM, 100%.
NHBoc
CO2H
NHBoc
CO2Me
b,c
a
R
R
R
CHO
65
Scheme 2. Reagents and conditions: (a) methyl 2-(t-butoxycarbonyl)-2-(dimethoxyphosphoryl) acetate, tetramethylguanidine, DCM, 0 °C–rt, 2 h, 55–82%; (b) 1% Rh-(R,R)-
DuPhos, MeOH:EtOAc, 40 psi H2, 12 h, 88–96%; (c) LiOH, H2O:THF:MeOH, 0 °C, 6 h, 90–96%, >95% ee.
NR1R2
c,d
CO2Me
CO2Me
COOH
a,b
R
R
R
67
66
Scheme 3. Reagents and conditions: (a) paraformaldehyde, 10% NaOMe, DMSO, rt, 12 h, 51–98%; (b) MsCl, TEA, DCM, 0 °C–rt, 12 h, 95%; (c) NR1R2, THF, 0 °C, 12 h; Boc2O, rt,
6 h, 72–91%; (d) LiOH–H2O, THF/MeOH/H2O, 0 °C–rt, 4 h, 86–92%.
NHBoc
NH2
R
R
O
O
N
H
N
2HCl
N
N
N
N
N
2HCl
N
N
a
b-c
N
N
N
N
N
N
H
PhO2S
PhO2
S
69
68
70
Scheme 4. Reagents and conditions: (a) HBTU, Hünig’s base, amino acid, DCM, 4 h, 88–99%; (b) LiOH–H2O, THF/MeOH/H2O, 0 °C–rt, 4 h, 88–96%; (c) 4 N HCl, DCM, rt, 4 h, 92–
99%.
oxygen of Asp292 is 3.5 Å. The 4-Cl phenyl group occupies a small
hydrophobic pocket under the P-loop that is formed when Phe161
is displaced toward the C-helix. The 4-Cl group appears nearly
ideal, given its relatively high C log P and small size.
In vitro ADME evaluation of many analogs revealed 54 as a can-
didate for further evaluation. Although 54 exhibited moderate cell
potency (cell IC50 = 160 nM), it also displayed low predicted clear-
ance (3.4 mL/min/kg, human hepatocytes), and assessment of plas-
ma protein binding in both human and mouse models suggested
the potential for high free fraction (human 65%, mouse 66% bound).
The Caco-2 permeability was measured for 54 at 6.8 Â 10À6 cm/s,
(apical to basolateral) and 26.1 Â 10À6 cm/s for the reverse direc-
tion, (basolateral to apical). The modest asymmetry suggested
some form of active efflux, most likely mediated by P-glycoprotein
transporters. The solubility of 54 was excellent at greater than
50 mg/mL (at pH 6.5 and 7.4). The predicted low clearance, high
free fraction, and excellent solubility properties of 54 suggested
it would be suitable for use in proof-of-concept studies in human
tumor mouse xenograft experiments.
The U87 human glioblastoma tumor cell line is PTEN negative
Figure 3. X-ray structure of 50 bound to Akt1, solved at 2.7 Å resolution (PDB code:
and displays a high level of Akt phosphorylation.10 U87 tumor
3OCB).14

J. F. Blake et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5607–5612
5611
xenografts implanted in female nude mice showed that p-PRAS40
Cl
Cl
Cl
NH2
NH2
NH2
levels decreased to 15% of control at 1 h (normalized to total Erk)
following ip injection of 20 mg/kg 54 (Fig. 4). At 4 h, the p-PRAS40
levels were still only 40% of control, but were starting to recover.
O
N
O
N
O
N
N
N
N
N
N
N
Plasma levels of 54 at 1 h were ca. 3.8
0.2 M at 4 h, which was consistent with the observed PD effect.
Following the initial proof-of-concept results, we undertook tol-
lM, and were less than
l
erability studies in preparation for more advanced tumor growth
inhibition experiments. Unfortunately, subcutaneous (sc) injection
of 54 in male CD-1 mice ranging from 20 to 60 mg/kg uniformly
produced death by ca. 4 h. Screening of 54 against a broad panel
of kinases found the compound displayed potent inhibition versus
N
H
N
H
N
H
N
46
N
N
60
61
13
1.2
4.3
PKA/Akt1
CaMKIV, PKA, PDK1, PKC(
(>90% inhibition at 1
M).11 To see if the poor tolerability was
due to the overall pharmacophore rather than an on target effect,
we evaluated 59, a weak inhibitor (cell IC50 = 11.8 M) at doses
c, bI, g, h), p70S6K, ROCK1, and AMPK
Figure 5. Prototype compounds with variable PKA/Akt1 selectivity. Ratio is
l
calculated from PKA/Akt1 enzyme IC50s.
l
ranging from 20 to 100 mg/kg, via sc injections. This compound
was well tolerated, suggesting that the overall scaffold was not
inherently problematic. The kinase inhibition profile of 59 showed
potent inhibition of PKA, MSK1, and p70S6K (>90% inhibition at
Ala230 of Akt1; this change may allow adjustment of the gate-
keeper and surrounding residues to accommodate a larger ligand
in Akt1. Also, the substitution of Leu (PKA) for Met281 at the base
of the hinge region tends to afford less space in PKA. Given the
above profiles and tolerability issues, we decided to focus our ef-
forts on alternative hinge binding cores that offered a better kinase
selectivity profile; forthcoming papers will address these selectiv-
ity issues.
We have described the discovery and optimization of a series a
pyrrolopyrimidine based pan inhibitors of Akt. The compounds dis-
play potent enzyme and cell based inhibition of our primary tar-
gets Akt1/2/3. Additionally, the compounds display excellent
knockdown of p-PRAS40 in tumor xenografts, combined with high
solubility and good ADME properties. While this profile is encour-
aging, the lack of selectivity against related kinases, in particular
PKA and ROCK1/2 render them poorly tolerated and unsuitable
for development as therapeutic agents.
1 lM). Interestingly, 55 (cell IC50 = 4.2 lM) was not tolerated using
the above paradigm (MTD <20 mg/kg, ip). Kinase panel screening
of 55 revealed significant inhibition of PKA IC50 = 1 nM, with
MSK1, PRK2, PRKG1, PrKX, ROCK1/2, Rsk1-4, CHK2, p70S6K, and
MRCKb all showing greater than 90% inhibition at 1 lM. This sug-
gested that some off-target activity, likely kinase-related, is the
cause of the poor tolerability of these inhibitors, and that develop-
ment of a selective Akt inhibitor would be better tolerated. Sup-
porting this notion, MK-2206, which is
a highly selective
allosteric Akt inhibitor, is reported to be well tolerated in preclin-
ical animal models.12
As documented above, the pyrrolopyrimidines tended to posses
potent inhibition of undesirable kinases (i.e., ROCK1/2, PKA, etc.),13
though a few examples did show a more selective profile. In partic-
ular, 61 showed PKA IC50 = 278 nM, with PKA/Akt1 = 13 (Fig. 5).
Interestingly, selectivity (PKA/Akt1) in this series increases from
1.2 for the 5-methyl (46), to 4.3 for the 6-methyl (60). For the qui-
nazoline series of compounds, the PKA/Akt1 ratio tended to be ca. 7
for most analogs, though 25 showed a slightly higher ratio of 12.
All of these results suggested that increased steric bulk near the
gatekeeper residue tended to improve the selectivity profile, rela-
tive to PKA. We note that PKA has a valine residue equivalent to
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.08.053.
References and notes
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6. Inhibition of Akt1, Akt2, Akt3, and PKA was determined using the IMAP format.
A detailed description of the assay format is provided in the Supplementary
data.
7. PDB Code 1O6K: Yang, J.; Cron, P.; Good, V. M.; Thompson, V.; Hemmings, B. A.;
Barford, D. Nat. Struct. Biol. 2002, 9, 940.
8. Docking studies were performed using the Glide program (Glide V4.5;
Schrödinger, L.L.C.: New York, NY, 2005) Friesner, R. A.; Banks, J. L.; Murphy,
R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley,
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9. The cell-based assay monitored the phosphorylation of Thr246 on PRAS40 in
LNCaP cells. A detailed description of the assay format is provided in the
Supplementary data.
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D. L. Proc. Natl. Acad. Sci. 2001, 98, 4622.
Figure 4. Evaluation of 54 dosed 20 mg/kg ip in the U87 human glioblastoma
11. The inhibition against
a panel of kinases was determined at Upstate,
xenograft model, results of four experiments. p-PRAS40 is normalized to total Erk.
Charlottesville, VA (256 total kinases screened).

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J. F. Blake et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5607–5612
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