Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor Based on Sulfonyl-Substituted Morpholinopyrimidines

Article abstract of DOI:10.1021/acsmedchemlett.8b00167

The discovery and optimization of a series of 2-morpholino-pyrimidine derivatives containing various sulfonyl side chains at the C₄ position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory activity against PI3Kα/β/γ/δ (IC₅₀ = 20/376/204/46 nM) and mTOR (IC₅₀ = 189 nM), potent functional suppression of AKT phosphorylation (IC₅₀ = 196 nM), and excellent antiproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation indicate that a cyclopropyl ring on the C₄ sulfone chain and a fluorine on the C₆ aminopyridyl moiety are responsible for its maintained PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HT-29 colorectal carcinoma xenograft model at the daily dose of 3.75 and 7.5 mg/kg relative to BKM120 at the dose of 15 and 30 mg/kg.

Full text of DOI:10.1021/acsmedchemlett.8b00167

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Letter
Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor
Based on Sulfonyl Substituted Morpholinopyrimidines
Sida Shen, Xiangyu He, Zheng Yang, Liang Zhang, Yingtao Liu, Zhiyuan
Zhang, Weiwei Wang, Wei Liu, Yufeng Li, Dong Huang, Kai Sun, Xiaojing Ni,
Xu Yang, Xinxin Chu, Yumin Cui, Qiang Lv, Jiong Lan, and Fusheng Zhou
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00167 • Publication Date (Web): 25 Jun 2018
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Discovery of an Orally Bioavailable Dual PI3K/mTOR Inhibitor
Based on Sulfonyl Substituted Morpholinopyrimidines
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Sida Shen, Xiangyu He, Zheng Yang, Liang Zhang, Yingtao Liu, Zhiyuan Zhang, Weiwei Wang, Wei
Liu, Yufeng Li, Dong Huang, Kai Sun, Xiaojing Ni, Xu Yang, Xinxin Chu, Yumin Cui, Qiang Lv,
Jiong Lan, Fusheng Zhou*
Yangtze River Pharmaceutical Group, Shanghai Haiyan Pharmaceutical Technology Co. Ltd., No. 8, 67 Libing Road,
Shanghai 201203, China
KEYWORDS: phosphoinositide-3-kinase, mammalian target of rapamycin, dual PI3K/mTOR inhibitor, morpholino-
pyrimidine.
ABSTRACT: The discovery and optimization of a series of 2ꢀmorpholinoꢀpyrimidine derivatives containing various sulfonyl side
chains at the C4 position led to the identification of compound 26 as a potent dual PI3K/mTOR inhibitor. It exhibited high inhibitory
activity against PI3Kα/β/γ/δ (IC50 = 20/376/204/46 nM), mTOR (IC50 = 189 nM), potent functional suppression of AKT phosphoryꢀ
lation (IC50 = 196 nM), and excellent antiꢀproliferative effects on a panel of cancer cells. Enzymic data and modeling simulation
indicate that cyclopropyl ring on the C4 sulfone chain and fluorine on the C6 aminopyridyl moiety are responsible for its maintained
PI3K activity and enhanced mTOR potency, respectively. Furthermore, compound 26 exhibited higher efficiency in the HTꢀ29
colorectal carcinoma xenograft model at the daily dose of 3.75 mg/kg and 7.5 mg/kg relative to BKM120 at the dose of 15 mg/kg
and 30 mg/kg.
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The phosphatidylinositol 3ꢀkinase (PI3K)ꢀprotein kinase B
(AKT)ꢀmammalian target of rapamycin (mTOR) transduction
pathway plays a critical role in a diverse set of cellular funcꢀ
tions, including cell growth, proliferation, motility, differentiaꢀ
tion, and survival, which is often constitutively dysregulated in
various human cancers, providing validated therapeutic targets
associated with a wide range of human malignancies.1 PI3Ks
can be divided into class I, II, and III according to their strucꢀ
tural characteristics and substrate preferences.2 The most studꢀ
ied class I PI3K is a heterodimer protein that is composed of a
catalytic subunit (p110α, p110β, p110δ, and p110γ) and a regꢀ
ulatory subunit (p85, p101, or p87).3 The p110 catalytic subuꢀ
nits are able to convert phosphatidylinositol diphosphate
(PIP2) to phosphatidylinositol triphosphate (PIP3), which
leads to the subsequent activation of serineꢀthreonine kinase
AKT in terms of phosphorylation of AKT.4 The downstream
kinase mTOR, a central regulator of cell growth and proliferaꢀ
tion, can be further activated by phosphorylated AKT
(pAKT).5 Compared with individually targeting PI3K or
mTOR, dual inhibition of PI3K and mTOR has recently been
proposed to represent a more effective approach for cancer
therapy, since this strategy can directly target the most comꢀ
monly mutated kinaseꢀPI3K (which is generally encoded by
the gene PIK3CA in the catalytic site of the p110α subtype6)
while overcoming multiple mTORꢀrelated negative feedback
loops that a selective mTOR inhibitor usually fails to repress.7
NCT01633060).8, The C6 aminopyridyl moiety on BKM
interacts via hydrogen bonding with Asp836, Asp841, and
Tyr867 and the 2ꢀmorpholine oxygen forms an important hyꢀ
drogen bond to the hinge Val882 NH that is considered as an
identical group for PI3K potency (Figure 1).8 A variety of
structural modification have been done focused on the reꢀ
placement of its pyrimidine core scaffold and C6 aminoꢀ
pyridyl moiety with different bicyclic cores and aromatic
urea/indole side chains, respectively, and anilines and amiꢀ
noheterocycles are predominant substitutions at the core pyꢀ
rimidine C4 position that orient towards solvent without any
specific hydrogen bonding.8, 10ꢀ12 The discovery of morphoꢀ
linopyrimidine based selective mTOR inhibitor AZD3147
from Astra Zeneca indicates that the NH groups on C6 phenylꢀ
thiourea or indole side chain are critical to engage productive
interactions with glutamic acid present in mTOR but not PI3K,
while C4 sulfonyl side chains do not participate any specific
interaction (Figure 1).13, 14, 15 Thus, C4 positions at the core
pyrimidine of both mTOR inhibitors and PI3K inhibitors can
consider as flexible sites for generating new ligands with
druggable properties and retained potency where are capable
to tolerate a range of substituents.
NVPꢀBKM120 (BKM, Figure 1), a compound with a pyrimiꢀ
dine scaffold developed by Novartis AG, displayed a potent
and selective class I PI3K inhibition over many other related
kinases and is undergoing phase III clinical trials for breast
cancer treatment (NCT01572727, NCT01610284, and
Figure 1. The design of a novel PI3K/mTOR dual inhibitor 26.
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Herein, we describe a hybridization approach to discover novꢀ
decrease in activity relative to the parent compound 6. In the
meanwhile, the (S)ꢀ3ꢀmethylmorpholine analog 11 maintained
enzymic and cellular effects comparable to those of 6. Further
exploration of the (S)ꢀ3ꢀmethylmorpholine fragment paired
with gemꢀdimethyl, cyclobutyl, and cyclopentyl substituents
adjacent to the sulfone side chain (in compounds 12ꢀ14)
turned out a consistent 2ꢀfold enhancement in enzymic potenꢀ
cy. Moreover, this optimization identified compound 13 with
low IC50 values of 93 nM and 78 nM against T47D and MCFꢀ7
in MTT cell proliferation assays, respectively. Another selecꢀ
tion of analogs was made to explore replacement of the termiꢀ
nal methyl group of the sulfone with ethyl, isopropyl, and
phenyl groups (entries 15ꢀ23). The ethyl and isopropyl termiꢀ
nal groups did not lead to better activity (compounds 15ꢀ18),
even though they were combined with the favorable cycloproꢀ
pyl or gemꢀdimethyl sulfonyl moieties. Compound 20 featurꢀ
ing a terminal phenyl group combined with gemꢀdimethyl
showed low nanomolar activity against PI3Kα, but it was relaꢀ
tively weak in the cellular assessment. Interestingly, cellular
potency was significantly enhanced once one extra fluorine
atom was located at the orthoꢀposition of phenyl ring adjacent
to the sulfone (compound 23). Replacement of the trifluoroꢀ
methyl substituent on the aminopyridyl moiety with fluorine
led to a slightly decrease in potency against PI3Kα, however
the antiꢀproliferative effects of the resulting compounds 24ꢀ27
were dramatically elevated, especially in the (S)ꢀ3ꢀ
methylmorpholine based analogs 26 and 27, which were found
to be 10 times more active than BKM against T47D and
MCFꢀ7 cells. Additionally, good corrections were observed
between cellular pꢀAKT inhibition in PCꢀ3 cells and antiproꢀ
liferation results in T47D (R2 = 0.88) and MCFꢀ7 cells (R2 =
0.92) (Figure S1) which demonstrates that pꢀAKT inhibition is
responsible for the cellular antiꢀproliferative effects even if in
the different cells. Nevertheless, 2D plot of biochemical
PI3Kα activity and cellular pꢀAKT inhibition doesn’t show a
nice linear regression (R2 = 0.53) that may be related to disꢀ
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el morpholinopyrimidines based PI3K inhibitors by replacing
the C4 morpholine moiety on the BKM with sulfonyl portion
taken from the selective mTOR inhibitors. Structureꢀactivity
relationship (SAR) studies conducted on twentyꢀseven new
analogs lead to the identification of compound 26 (Figure 1), a
potent dual inhibitor of PI3K and mTOR that exhibits remarkꢀ
able cellular antiꢀproliferative effects compared to BKM. Enꢀ
zymic data and modeling simulation fully explain that cycloꢀ
propyl ring on the C4 sulfone chain and fluorine on the C6
aminopyridyl moiety are responsible for its maintained PI3K
activity and enhanced mTOR potency, respectively. Furtherꢀ
more, compound 26 also exhibits encouraging ADMET propꢀ
erties and significant in vivo tumor growth inhibitory efficacy
in the HTꢀ29 colorectal carcinoma xenograft mouse model
compared to BKM.
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The structural modifications were focused on the sulfonyl side
chains with different substituents on the methylene unit and
the terminal area. The detailed synthetic procedures and specꢀ
trum data of final products 1ꢀ27 are provided in supporting
information (Scheme S1). all the new analogs were initially
evaluated for in vitro activities by testing PI3Kα enzymic inꢀ
hibition, the resulting suppression of pAKT in PCꢀ3 cells, and
subsequent antiproliferation assays on breast cancer cell lines
T47D and MCFꢀ7 carrying a PIK3CA H1047R mutation and
E545K mutation, respectively (Table 1).16 The exploration of
alkylation or fluorination at the methylene unit of the sulfone
portion led to an improvement in potency in most cases (enꢀ
tries 1ꢀ9), whereas these trends weren’t observed in isopropyl
(4) and cyclohexyl (9) analogs indicating a limit to the size of
the substituent. Among these analogs, the IC50 values of the
gem-dimethyl (5), cyclopropyl (6), and cyclobutyl (7) analogs
were lower than 20 nM against PI3Kα, accompanied by an
improvement in cellular phosphorylation of AKT and antiꢀ
proliferation in comparison with the reference compound
BKM. The replacement of morpholine with (R)ꢀ3ꢀ
methylmorpholine (in compound 10) resulted in a 14ꢀfold
tinct
permeability.
Table 1. Structure−Activity Relationship Studies at the R1, R2, and R3 Groups.a
O
N
R2
R1
R3
N
N
N
H2N
PI3Kα
IC50 (ꢁM)
PCꢀ3 pAKT
IC50 (ꢁM)
T47D
IC50 (ꢁM)
MCFꢀ7
IC50 (ꢁM)
Compound
R1
R2
R3
H
H
CF3
CF3
0.189
3.01
1.668
1.155
1.513
1.139
1
2
0.056
0.025
2.446
H
CF3
0.846
0.513
0.408
3
H
H
H
CF3
CF3
CF3
0.218
0.013
0.013
n/db
n/d
n/d
4
5
6
0.312
0.319
0.058
0.167
0.224
0.283
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H
H
CF3
CF3
0.015
0.042
0.248
0.384
0.138
0.218
0.134
0.34
7
8
1
2
3
4
5
6
7
8
H
CF3
CF3
0.321
0.223
n/d
n/d
n/d
n/d
n/d
n/d
9
(R)ꢀCH3
10
9
(S)ꢀCH3
(S)ꢀCH3
CF3
CF3
0.009
0.006
0.546
0.306
0.129
0.175
0.112
0.214
11
12
10
11
12
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26
27
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(S)ꢀCH3
(S)ꢀCH3
CF3
CF3
0.006
0.022
0.184
0.674
0.093
0.139
0.078
0.159
13
14
H
H
H
CF3
CF3
CF3
0.013
0.040
0.058
0.301
0.947
0.43
0.225
0.552
0.16
0.295
0.512
0.437
15
16
17
H
H
H
CF3
CF3
CF3
0.065
0.026
0.009
1.178
0.668
1.548
1.063
0.324
0.478
0.599
0.513
0.897
18
19
20
H
H
H
CF3
CF3
CF3
0.057
0.014
0.007
1.275
0.606
0.367
0.619
0.242
0.129
0.5715
0.286
0.184
21
22
23
H
F
F
F
F
0.041
0.066
0.010
0.369
0.215
0.196
0.062
0.123
0.03
0.027
0.104
0.011
24
25
26
H
(S)ꢀCH3
(S)ꢀCH3
0.020
0.041
0.121
0.365
0.033
0.286
0.015
0.206
27
ꢀ
BKM
ꢀ
aIC50, the mean value of duplicate measurements; bn/d: not determined.
Compounds 1, 6, 11, and 26 were selected for further characꢀ
terization in other three class I PI3K subtypes as well as
mTOR. The results shown in Table 2 indicate cyclopropyl ring
presented on the sulfone chain plays important role to mainꢀ
tain comparable Class I PI3K relative to BKM. Notably, conꢀ
verting the trifluoromethyl group (11) to fluorine (26) on the
C6 aminopyridyl moiety led to a 11ꢀfold potency increase
against mTOR and 4ꢀfold improved potency at PI3Kδ subꢀ
types. As the sulfone side chain is also present in inhibitors of
Ataxia telangiectasia mutated and RAD3ꢀrelated (ATR) beꢀ
longing to phosphatidylinositol 3ꢀkinaseꢀrelated kinase
(PIKK) family,17 the capability of compounds 1, 6, 11, and 26
to impact the ATR cellular activity in terms of inhibition of
phosphorylation of Chk1 Serꢀ345 were also evaluated in HTꢀ
29 cells. 1, 6, 11, and BKM were found to be inactive up to 10
µM, while 26 shows slight inhibition at the concentration of
10 µM (Figure 2).
Table 2. Class I PI3K and mTOR inhibitory activities of comꢀ
pounds 1, 6, 11, and 26.a
Enzyme IC50 (µM)
Compound
PI3Kα PI3Kβ PI3Kγ PI3Kδ mTOR
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that the elevated mTOR activity is responsible for its dramatiꢀ
cally improved cellular antiꢀproliferative effects.
0.189
0.016
0.016
0.020
0.040
n/db
n/d
n/d
13.98
1.680
2.120
0.186
1.981
1
1
2
3
4
5
6
7
8
0.314
0.264
0.376
0.234
0.288
0.164
0.204
0.372
0.240
0.197
0.046
0.125
6
To better understand the interactions with targeted proteins,
docking simulations were performed for compound 26 with
PI3Kα, mTOR, and tubulin (Figure 4). The binding mode of
26 to PI3Kα is very similar to that of BKM, which is responꢀ
sible for similar potency against PI3Kα. The morpholine forms
a key hydrogen bond with Val851 (Val2240 on mTOR) in the
hinge region, the amino group at the 2ꢀposition of the pyridine
engages in another hydrogen bond with Asp810 (Asp2195 on
mTOR), the sulfone side chain occupies the ribose pocket, and
the fluorine at the 4ꢀposition of the pyridine is involved in an
attractive electrostatic interaction with Lys802. At the same
position on mTOR, the residue is Glu2190 which causes a
repulsive force that twists the binding of compound 26 and
thereby enhances the compound’s potency at mTOR. Moreoꢀ
ver, the overlapped docking poses with tubulin indicate that
cyclopropyl group of 26 is too big to accommodate the tubulin
binding site due to the steric hindrance with Lys352, leading
to a binding displacement from BKM and weaker binding to
tubulin, which may differentiate 26 with BKM.
11
26
BKM
aIC50, the mean values of duplicate measurements. n/d: not deꢀ
b
termined.
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Figure 2. Effect of compounds 1, 6, 11, and 26 on ATR activity
in the presence of DNA damage. HTꢀ29 were preꢀtreated with
indicated compounds for 1 h, DNA damage was induced by expoꢀ
sure to camptothecin. ATR activity was measured by detecting
phosphorylation of substrate Chk1, total Chk1 and βꢀactin were
shown as internal control. KUꢀ60019 (KU) is a specific inhibitor
of ATM/ATR and DNAꢀPK.
Thirteen potent compounds (3, 5ꢀ7, 13, 16, 18, 20, 23ꢀ27)
were used for metabolic stability study in human and mouse
liver microsomes to identify metabolically stable compounds
for in vivo studies. The results shown in Table S1 indicate that
the compounds containing trifluoromethyls exhibit a signifiꢀ
cantly low metabolic stability relative to BKM (Clint: human,
10.86 mL/min/kg; mouse, 151.33 mL/min/kg) except the
compound 6 (Clint: human, 9.86 mL/min/kg; mouse, 185.15
mL/min/kg). A cyclobutane ring on the methylene unit, a (S)ꢀ
3ꢀmethylmorpholine moiety, and an aromatic terminal groups
are particularly detrimental to metabolic stability in this series.
However, aminofluoropyridines 24ꢀ27 exhibited comparable
or much better liver microsomal stability both in human (Clint:
5ꢀ16 mL/min/kg) and mouse (Clint: 40ꢀ140 mL/min/kg) in
comparison with BKM. Given its enhanced mTOR potency
and metabolic stability, we were interested in advancing comꢀ
pound 26 into more characterization.
A panel of cell lines was chosen to carry out antiproliferation
screening to compare 26 and BKM. The treatment of 26
turned out 2.5ꢀfold to 18.7ꢀfold improvement against different
cells (Figure 3A, Table S2), while stronger cytotoxicity
against HUVECs (26, IC50 = 0.108 µM; BKM, IC50 = 0.886
µM) was also observed without certain cell selectivity. It is
known that BKM shows effects on the destabilization of miꢀ
crotubule that contributes to its therapeutic intervention toꢀ
gether with its PI3K inhibition.18 we thought that this property
might transfer to the new hybrid analogs due to their structural
similarity. A doseꢀresponse cell cycle study in HTꢀ29 cell
showed BKM accumulated cells dominantly in G2/M fraction
as expected that leads to mitotic arrest or apoptosis (Figure
3C). In contrast, the treatment of 26 arrested cells in the G1
fraction which acts same as cytostatics (Figure 3B). In addiꢀ
tion, no obvious effect of 26 at 10 µM concentration was obꢀ
served in an offꢀtarget test containing twentyꢀeight different
kinases (Table S3) and 26 exhibited comparable results with
BKM against the mutant PI3Kα E542K, E545K, H1047R
subtype inhibition. Overall, the experimental results elucidate
Figure 3. PI3Kα mutant enzymic data, cancer cell panel screening
(A), and cell cycle distribution in HTꢀ29 cells (BꢀD) of 26.
Further ADMET profiling demonstrates compound 26 does
not inhibit the most common cytochrome P450 enzymes (CYP)
1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 (IC50 values > 10
µM, Table S4). In vitro evaluation on human hERG channel
current indicated a minimal risk of 26 induced long QT synꢀ
drome (IC50 > 30 µM, Figure S2). The Cacoꢀ2 permeability
assay determined 26 as a high permeable compound on both
sides (Papp >10 × 10ꢀ6 cm/s) with favorable efflux ratio (Papp
(BꢀA)/ Papp (AꢀB) = 0.66, Table S5), which is supportive for its
excellent cellular potency. A pharmacokinetic (PK) profiling
was further performed for compound 26 in CD1 mice. As preꢀ
sented in Figure 5 (left), intravenous administration of 26 to
mice at 5 mg/kg (dissolved in 15% Captisol) exhibited a simiꢀ
lar clearance rate (15.2 mL/min/kg), volume of distribution
(1.40 L/kg), and halfꢀlife (1.59 h) relative to the corresponding
parameters of BKM disclosed in the literature.8 Oral adminꢀ
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istration to mice at 10 mg/kg (dissolved in 15% Captisol)
yielded a high Cmax (2984 ng/mL) and plasma exposure
(AUClast = 10379 h*ng/mL) with an excellent oral bioavailaꢀ
bility (F% = 94.6%).
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Figure 4. Docking poses of 26 (orange) with PI3Kα (A, PDB entry: 4l23), mTOR (B, PDB entry: 4jt6), and tubulin (C, 26: cyan, BKM:
yellow, entry: 5m7e).
Figure 5. PK parameters and efficacy studies of 26. (left) Male CD1 mice (n =18) were assigned to 2 groups: 9 animals were administered
via oral gavage (10 mg/kg) and 9 animals were administrated via tail vein injection (5 mg/kg). Blood samples were collected at 0.083,
0.25, 0.5, 1, 2, 4, 8 and 24 h post dose (n = 3 mice per time point). (middle) Balb/c nu/nu mice bearing HTꢀ29 xenograft tumors were treatꢀ
ed with vehicle, BKM (15 or 30 mg/kg), or 26 (3.75 or 7.5 mg/kg) by daily oral gavage for 27 days when the mean tumor size was around
240 mm3. The estimated tumor volume was plotted versus time. The tumor growth inhibition (TGI) was calculated after 27ꢀday treatment
(26, 3.75 mpk, TGI = 54.4%, *p = 0.02; 26, 7.5 mpk, TGI = 72.9%, *p = 0.02; BKM, 15 mpk, TGI = 39.4%, *p = 0.02; BKM, 30 mpk,
TGI = 55.7%, *p = 0.04). (right) The body weight change (BWC) was measured, calculated and plotted versus time. All data are presented
as the mean ± SEM (n = 6). Dunnett's multiple comparison test. *<0.05.
With these encouraging in vitro effects and preliminary
ADMET profiling, compound 26 was tested in in vivo efficacy
studies in the end. HTꢀ29 colorectal carcinoma xenograft
mouse model carrying the PIK3CA P449T mutation was seꢀ
lected for our efficacy studies, as the PI3K/AKT/mTOR pathꢀ
way is being considered as a potential therapeutic target for
the treatment of colorectal cancer.19 Considering the higher
cytotoxicity and stronger antiꢀproliferative effects of 26, 4ꢀfold
lower doses (3.75 and 7.5 mg/kg) were selected in comparison
with BKM at the doses of 15 and 30 mg/kg, respectively (Figꢀ
ure 5, middle). BKM only produced 39.4% tumor growth inꢀ
hibition (TGI) with the treatment of 15 mg/kg, while better
single agent efficacy (TGI = 54.4%) was observed with 26 at
daily oral doses of 3.75 mg/kg for 27 days in a wellꢀtolerated
manner, which was comparable to the result with BKM at the
dose of 30 mg/kg (TGI = 55.7%). Interestingly, the proliferaꢀ
tion assay result of BKM (IC50 = 1.186 ꢁM) in HTꢀ29 cell was
also about 7.3 folds higher than 26 (IC50 = 0.163 ꢁM) (Table
S2) which suggests a hint of correlation between in vivo tumor
suppression and in vitro antiꢀproliferation activity, although
drug exposure in tumor tissue and in vivo target modulation
haven’t been determined. The 7.5 mg/kg group of 26 disꢀ
played more significant TGI (72.9%) All animals were survivꢀ
al after 27ꢀday treatment, whereas 15% weigh loss was obꢀ
served in 26 7.5 mg/kg group (Figure 5, right). Notably, 60
mg/kg BKM was also enrolled at the beginning of in this
study that was terminated after 10ꢀday treatment due to serious
toxicity (weigh loss >25%, Figure S3).
In summary, we have designed and synthesized a new series
of 6ꢀaminopyridyl, 4ꢀsulfonyl, 2ꢀmorpholinoꢀpyrimidine core
analogs as novel PI3K inhibitors. Through the SAR profiling
of different substituents at the methylene unit and the terminal
region of sulfonyl side chains, as well as the combination with
different morpholino and aminopyridyl moieties, we successꢀ
fully addressed the identification of orally bioavailable comꢀ
pound 26, which exhibited potent enzymic activity against
Class I PI3K and PI3Kα mutant isoforms, improved mTOR
potency, good suppression of pAKT in cellular assays, and
promising pharmacokinetic parameters. Significantly, comꢀ
pound 26 was found to be much more effective both in in vitro
and in vivo studies compared to BKM.
ASSOCIATED CONTENT
Supporting Information
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ACS Medicinal Chemistry Letters
M.; Kaufman, S.; Crawford, K.; Chin, M.; Bussiere, D.; Shoemaker,
The Supporting Information is available free of charge on the
ACS Publications website.
K.; Zaror, I.; Maira, S. M.; Voliva, C. F., Identification of NVPꢀ
BKM120 as a Potent, Selective, Orally Bioavailable Class I PI3
Kinase Inhibitor for Treating Cancer. ACS Med. Chem. Lett. 2011, 2,
774ꢀ9.
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Supplementary figures and table, details of the synthetic chemisꢀ
try, docking studies, and biological assays (PDF)
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9. Maira, S. M.; Pecchi, S.; Huang, A.; Burger, M.; Knapp, M.;
Sterker, D.; Schnell, C.; Guthy, D.; Nagel, T.; Wiesmann, M.;
Brachmann, S.; Fritsch, C.; Dorsch, M.; Chene, P.; Shoemaker, K.;
De Pover, A.; Menezes, D.; MartinyꢀBaron, G.; Fabbro, D.; Wilson,
C. J.; Schlegel, R.; Hofmann, F.; GarciaꢀEcheverria, C.; Sellers, W.
R.; Voliva, C. F., Identification and characterization of NVPꢀ
BKM120, an orally available panꢀclass I PI3ꢀkinase inhibitor. Mol.
Cancer Ther. 2012, 11, 317ꢀ28.
AUTHOR INFORMATION
Corresponding Author
F. Z.: email: fushengz@haiyanpharma.com,
zhoufs2015@163.com.
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ORCID
Fusheng Zhou: 0000ꢀ0002ꢀ6277ꢀ906X;
Sida Shen: 0000ꢀ0002ꢀ0295ꢀ2545.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
Funding Sources
The work was sponsored by Shanghai Risingꢀstar Program
17QB401100.
ABBREVIATIONS
PI3K: phosphatidylinositol 3ꢀkinase; AKT: protein kinase B;
mTOR: mammalian target of rapamycin; PIP2: phosphatidylinosiꢀ
tol diphosphate; PIP3: phosphatidylinositol triphosphate; pAKT:
phosphorylated AKT; ADMET: absorption, distribution, metaboꢀ
lism, excretion, and toxicity; SAR: structureꢀactivity relationship;
PK: pharmacokinetics; AUC: area under curve; CYP: cytochrome
P450; hERG: human ether-a-go-go-related gene; i.v.: intravenous
administration; p.o.: oral administration; TGI: tumor growth inhiꢀ
bition.
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