Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR

Article abstract of DOI:10.1021/acsmedchemlett.8b00002

The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.

Full text of DOI:10.1021/acsmedchemlett.8b00002

Letter
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Discovery of Pyridopyrimidinones as Potent and Orally Active Dual
Inhibitors of PI3K/mTOR
Tao Yu,*,† Ning Li,† Chengde Wu,† Amy Guan,† Yi Li,† Zhengang Peng,† Miao He,† Jie Li,†
Zhen Gong,† Lei Huang,† Bo Gao,† Dongling Hao,† Jikui Sun,† Yan Pan,† Liang Shen,† Chichung Chan,†
Xiulian Lu,‡ Hongyu Yuan,‡ Yongguo Li,‡ Jian Li,† and Shuhui Chen†
†Domestic Discovery Service Unit, WuXi AppTec (Shanghai) Co. Ltd., 288 FuteZhong Road, Waigaoqiao Free Trade Zone, Shanghai
200131, China
‡Cisen Pharmaceutical Co. Ltd., Tongji Sci-tech Industrial Park, High-tech Industrial Development Zone, Jining, Shandong 272073,
China
S
* Supporting Information
ABSTRACT: The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel
class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity
against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic
profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.
KEYWORDS: PI3K, mTOR, dual inhibitor, anticancer
he phosphoinositide 3-kinases (PI3Ks) family is a class of
lipid kinases that is involved in cell growth, proliferation,
T
differentiation, and survival.1−3 The PI3Ks can be divided into
three classes (Class I, Class II, and Class III) according to the
structural characteristic, and the most important class I PI3Ks,
including four isoforms (p110α, p110β, p110δ, and p110γ), can
phosphorylate phosphatidylinositol diphosphate (PIP2) to
generate its corresponding triphosphate (PIP3), a potent
secondary messenger that results in the activation of the
downstream serine-threonine kinase Akt.4,5 Subsequent phos-
phorylation of AKT leads to the triggering of the pathway that
ultimately activates the mammalian target of rapamycin
(mTOR), which promotes cell growth and survival by
integrating signals from growth factors, nutrients, and cellular
energetics.6 Therefore, inhibitors of key kinases in the PI3K/
AKT/mTOR signaling pathway have been extensively identi-
fied for the treatment of cancer in recent years.7
Figure 1. Structure of GSK2126458 and 31.
Among them, GSK2126458 (Figure 1) has been identified as
a highly potent and orally bioavailable PI3K/mTOR dual
inhibitor and is currently in phase I clinical trials.14 The
reported cocrystal structure of GSK2126458 with PI3Kγ,14
which is highly homologous to other class I PI3K isoforms,
showed that the nitrogen in quinoline forms an important
hydrogen bond with Val882 in the hinge region. The pyridyl
nitrogen atom has a key interaction with a conserved water
molecule. The sulfonamide makes a strong charged interaction
with Lys833. In addition, the difluorophenyl group occupies a
hydrophobic region in the ATP binding site back pocket of the
Since dual suppression of PI3K/mTOR may most effectively
prevent the PI3K signaling cascade transduction, overcome
feedback loops, and block PI3K-independent mTOR activation,
the development of PI3K/mTOR dual kinase inhibitors
represents a beneficial therapeutic intervention strategy in
cancer treatment.8 To this end, several research groups have
been focusing their efforts on the development of small
molecular PI3K/mTOR inhibitors in the literature.9−18
Received: January 3, 2018
Accepted: February 27, 2018
Published: February 27, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.8b00002
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ACS Medicinal Chemistry Letters
Letter
Figure 2. Inhibition of pAKT in MCF-7 cell at 1 μM concentration.
Table 1. Structure−Activity Relationship with R1 and R2
Groups
MCF-7 cell
p-Akt %
inhibition at
1 μM
MCF-7
cell p-Akt MCF-7 cell
IC50
(nM)
p-p70s6k
compd
R1
R2
IC50 (nM)
7
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OEt
Ph
95
95
96
94
94
95
96
94
94
98
98
96
76
53
78
60
81
82
85
81
86
92
91
98.8
80.7
48.8
57.4
48.7
54.1
67.0
141.0
23.9
16
197.9
105.8
223.4
245.7
163.3
138.0
64.0
8
4-FC6H4
4-ClC6H4
4-CNC6H4
4-CF3C6H4
4-OMeC6H4
3-FC6H4
2-FC6H4
2-MeC6H4
2,4-FC6H3
3,5-FC6H3
2,5-FC6H3
cyclopropyl
Et
Figure 3. Modeled structure of compound 4 with PI3Kα.
9
10
11
12
13
14
15
4
kinase. The pyridazine group seemed to point in the solvent
region and not contribute to binding interaction.
On the basis of the binding mode, our design strategy was to
keep pyridyl sulfonamide moiety unchanged initially, and to
remove the pyridazine group to reduce molecule weight and
number of aromatic rings, and to search for a novel hinge
binder. Herein, we describe the discovery of a novel
pyridopyrimidinone scaffold and our early lead optimization
efforts in this series, resulting in N-(5-(3-chloro-4-oxo-4H-
pyrido[1,2-a]pyrimidin-7-yl)-2-methoxypyridin-3-yl)-2,4-di-
fluorobenzenesulfonamide 31 as a highly potent dual PI3K/
mTOR inhibitor for in vivo studies (Figure 1).
>400
153.4
66
16
17
18
19
20
21
22
23
24
25
26
27
28
78.2
45
77.2
108.5
CF3CH2
2-FC6H4
2,4-FC6H3
2-FC6H4
4-FC6H4
2-FC6H4
2,4-FC6H3
2,4-FC6H3
2-FC6H4
Our primary optimization is focused on probing different
scaffolds that resemble a quinoline core, such as cinnoline,
pyrido[3,4-d]pyrimidine, 1,8-naphthyridine, and pyridopyrimi-
dinone. All synthesized compounds 1−4 were initially
evaluated for in vitro activities against PI3Kα by testing the
corresponding inhibition of pAKT in MCF-7 cell at a single
concentration (1 μM). Among the various heterocycles,
compound 4 was very attractive with a pAKT inhibition of
98% at 1 μM. Further replacing the “CH” of the
pyridopyrimidinone ring with a “N” led to 4H-pyrimido[1,2-
b]pyridazin-4-one derivative 5 and 4H-pyrazino[1,2-a]-
pyrimidin-4-one derivative 6, which exhibited a slightly higher
Me
Me
Me
Et
Et
Cl
32.8
34.4
>400
>400
Cl
TPSA and lower cLogP value, but showed poor inhibition of
pAKT relative to compound 4 (Figure 2).
Docking study of compound 4 with PI3Kα was carried out.19
As illustrated in Figure 3, the nitrogen atom of pyridopyr-
B
DOI: 10.1021/acsmedchemlett.8b00002
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ACS Medicinal Chemistry Letters
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Table 2. Structure−Activity Relationship with R3 Group
MCF-7 cell p-
p70s6k IC50
(nM)
MCF-7 cell p-Akt % MCF-7 cell p-
compd
R3
inhibition at 1 μM
Akt IC50 (nM)
29
30
31
OEt
Me
Cl
76
90
93
27.9
11.6
119
89.2
Table 3. In Vitro Activities of Compounds 4 and 31
compd
enzyme IC50 (nM)
4
31
PI3Kα/β/δ/γ
mTOR
3.1/−/−/−
3.4/34/16/1
4.7
19.2
MCF-7 cell IC50 (nM)
pAkt
16
11.6
p-p70s6k
66
89.2
Table 4. Mouse PPB and PK Profiles of Compounds 4 and
31
compd
PPB % bound (h, r, m)
4
31
99.5,
99.2,
98.1
>99,
>99,
99.5
iv (mouse) @ 1 mg/kg
po (mouse) @ 3 mg/kg
Cl (mL/min/kg)
Vdss(L/kg)
5.15
1.4
Figure 4. Modeled structures of compound 31 with PI3Kα and
mTOR.
0.443
1
0.472
3
T1/2 (h)
AUC0‑last (ng·h/mL)
Cmax (ng/mL)
Tmax (h)
3285
4083
0.333
13755
139
11883
5450
2.67
38568
108
AUC0‑last (ng·h/mL)
F%
imidinone formed a key hydrogen bond with hinge residue
Val850. The methoxy group from the pyridine moiety formed a
hydrogen bond with Lys802. Besides the hydrogen bonds,
pyridopyrimidinone also formed a π−π stacking interaction
with gatekeeper Tyr836.
Further in vitro biomarker studies demonstrated potent
suppression of Akt-S473 and p70s6k-T389 phosphorylation
(IC50 = 16 nM and 66 nM) in MCF-7 cells after 4 h of
incubation with compound 4, using ADP-Glo assay. Encour-
aged by this result, we commenced with an investigation on the
pyridyl moiety with different sulfonamides at 3-position and
substituents at 2-position of pyridine ring to obtain potent
PI3K/mTOR inhibitors. The biological data for compounds 4
and 7−28 are compiled in Table 1. All pyridopyrimidinone
derivatives (7−17) with substituted aryl sulfonamide exhibited
excellent inhibition of pAKT at 1 μM concentration. The
unsubstituted benzsulfamide 7 had 98.8 nM for PI3K cellular
activity and 197.9 nM for mTOR cellular activity. para-
Substitution with a small group, such as F (8), Cl (9), CN (10),
CF3 (11), or OMe (12), all increased PI3K cellular activity, but
with mixed effect on mTOR. meta and ortho-Substitution were
studied with less examples. meta-F-substituent (13) increased
both PI3K and mTOR activity to be equally potent (67 and 64
nM, respectively), while an ortho-F (14) decreased both
activities. ortho-Me (15) increased PI3K cellular activity by
approximately 5× with little effect on mTOR. Disubstitution
Figure 5. PC-3M xenograft model tumor growth curve and body
weight change (%).
patterns were studied with fluoro groups. All 2,4-(4), 2,5-(17),
and 3,5-(16) difluorosubstitutions increased PI3K and mTOR
C
DOI: 10.1021/acsmedchemlett.8b00002
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ACS Medicinal Chemistry Letters
Letter
Scheme 1. Synthetic Route of Compounds 4 and 7−28
cellular activity with 2,4-(4) being the most active for both
kinases. The aromaticity of benzene seemed to be required for
PI3K activity since replacement of phenyl with Et (19),
trifluoroethyl (20), or cyclopropyl (18) gave only 53−78%
inhibition at 1 μM. Replacement of the methoxy group on the
pyridine ring with methyl, ethyl, or ethoxyl all caused a decrease
of PI3K percent inhibition at 1 μM: methyl (22 vs 4, 23 vs 14,
and 24 vs 8), ethyl (25 vs 14, 26 vs 4), and ethoxyl (21 vs 14).
However, replacement by a Cl group resulted in an increase of
PI3K activity to about 30 nM (27 and 28) but destroyed
mTOR activity.
Based on the structure of compound 4, we conducted further
SAR studies on the pyridopyrimidinone moiety. In particular,
we examined the effect of ethoxyl, methyl, and chlorine at the
ortho-position of the carbonyl group on potency. As can be seen
from Table 2, the introduction of a chlorine or methyl group
had negligible effect on cell potencies. However, this effect
depends on the size of the substituent group, so the larger
ethoxy group substituted at the same position showed a lower
potency relative to compounds 30 and 31.
After this preliminary optimization of enzymatic and cellular
activities, we next evaluated in vitro and in vivo pharmacoki-
netic (PK) profiles (4 and 31). As presented in Table 4, they
each showed a high level of plasma protein-binding in human,
rat, and mouse. When the two compounds were administered
intravenously (iv) to mice at 1 mg/kg (in 10% DMSO/65%
PEG400/25% H2O for compound 4; in 10% DMSO/80%
PEG400/10% H2O for compound 31), compound 31 exhibited
a low clearance (1.4 mL/min/kg), a similar volume of
distribution (0.472 L/kg), a long half-life (3 h), and a high
AUC exposure relative to compound 4. When dosed orally
(po) in mouse at 3 mg/kg (in 10% DMSO/65% PEG400/25%
H2O for compound 4; in 10% DMSO/80% PEG400/10% H2O
for compound 31), a high Cmax (5450 ng·h/mL) and plasma
exposure with an excellent oral bioavailability were also
observed.
Further analysis of 31 docked into the models of PI3Kα and
mTOR indicated that an extra halogen bond with Cys2243 in
mTOR was formed, thereby explaining the increased enzyme
activity against mTOR (Figure 4).19
Among the various pyridopyrimidinone derivatives, com-
pounds 4 and 31 looked the most promising because of their
high potency in cell assays. In the meantime, their enzyme
activities against PI3Kα and mTOR were also examined, using a
HTRF assay.20 It is found that each of the two compounds
possessed appreciable in vitro inhibition of the enzyme,
especially 31 represents a novel scaffold for a potent dual
pan-PI3K/mTOR inhibitor, exhibiting strong IC50 values of
3.4/34/16/1 nM for PI3Kα/β/δ/γ and 4.7 nM for mTOR
(Table 3).
On the basis of its enzyme and cellular potencies and its
pharmacokinetic profile, compound 31 was taken forward for in
vivo efficacy studies (Figure 5). Evaluation of in vivo efficacy of
31 was performed in nude mice bearing PC-3M cancer tumors.
Compound 31 was administered @ 1, 3, and 10 mg/kg, po
doses, daily for 21 days (10 mice per group). In this PC-3M
xenograft tumor model, compound 31 exhibited dose-depend-
ent tumor growth inhibition, and significant in vivo efficacy was
observed when dosed 10 mg/kg, qd (as shown in Figure 5). In
these studies, compound 31 was also well tolerated, and no
D
DOI: 10.1021/acsmedchemlett.8b00002
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36 with 39 afforded a series of 4H-pyrido[1,2-a]pyrimidin-4-
one derivatives 4 and 7−28 (Scheme 1b).
Scheme 2. Synthetic Route of Compound 29−31
A similar route was also applied to synthesize compounds
29−31. As shown in Scheme 2, under Bredereck reaction
conditions, commercially available ethyl 2-ethoxyacetate 40 was
converted to the enamine product 41, and subsequent
treatment with 5-bromopyridin-2-amine 37 at 90 °C provided
7-bromo-3-ethoxy-4H-pyrido[1,2-a]pyrimidin-4-one 42
(Scheme 2a). Cyclization of 5-bromopyridin-2-amine 37 with
diethyl 2-methyl-3-oxosuccinate in refluxing EtOH, followed by
decarboxylation led to 7-bromo-3-methyl-4H-pyrido[1,2-a]-
pyrimidin-4-one 44 (Scheme 2b). In addition, treatment of 7-
bromo-4H-pyrido[1,2-a]pyrimidin-4-one 39 with NCS gave the
7-bromo-3-chloro-4H-pyrido[1,2-a]pyrimidin-4-one 45
(Scheme 2c). Finally, ethyoxyl-, methyl-, and chlorine-
substituted 7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one 42, 44,
and 45 were respectively reacted with pyridineboronic acid
pinacol ester 36a to provide the desired products 29−31.
In summary, we have designed and synthesized a new series
of 4H-pyrido[1,2-a]pyrimidin-4-one derivatives as potent and
orally active PI3K/mTOR dual inhibitors utilizing structure-
based design strategy. Through the exploration of different
sulfonamides in a pyridine ring and substituents at the 2-
position of the pyridine ring and at the ortho-position of
carbonyl group of 4H-pyrido[1,2-a]pyrimidin-4-one, we
successfully developed the SAR profile around this series,
resulting in the discovery of compound 31, which has shown
good enzyme activity against PI3K and mTOR and potent
suppression of Akt and p70s6k phosphorylation in cellular
assays. Furthermore, compound 31 also demonstrated
significant in vivo efficacy in a PC-3M tumor xenograft model.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.8b00002.
■
S
Experimental and characterization data for all new
compounds and all biological data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: yu_tao_001391@wuxiapptec.com.
■
ORCID
significant body weight loss was observed for all different
dosages.
Tao Yu: 0000-0002-3828-0365
Author Contributions
The manuscript was written by L.Y. All authors have given
approval to the final version of the manuscript.
Notes
Compounds 7−31, which are shown in the present Letter,
were prepared starting from commercially available materials, as
outlined in Schemes 1 and 2. Compounds 32 were reacted with
bis(pinacolato)diboron in the presence of Pd(dppf)2Cl2 and
KOAc in dioxane at 100 °C to afford the corresponding
pyridineboronic acid pinacol esters 33. Reduction of 33 with
Pd/C under hydrogenation conditions gave the pyridinamines
34, which were treated with different sulfonyl chlorides 35 in
pyridine to give the key intermediates 36 (Scheme 1a). This
synthetic sequence can be applied to the synthesis of various
substituted pyridineboronic acid pinacol ester by varying the
primary material or sulfonyl chloride. Treatment of 5-
bromopyridin-2-amine 37 with 2,2-dimethyl-1,3-dioxane-4,6-
dione in the presence of triethyl orthoformate generated the
imine 38, followed by cyclization in diphenyl oxide at 220 °C
leading to the 7-bromo-4H-pyrido[1,2-a]pyrimidin-4-one 39.
Suzuki reaction of different pyridineboronic acid pinacol esters
The authors declare no competing financial interest.
ABBREVIATIONS
■
PK, pharmacokinetics; SAR, structure−activity relationship;
PPB, plasma protein binding; IV, intravenous; PO, per oral;
AUC, area under curve; mpk, mg/kg
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