Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ

Article abstract of DOI:10.1021/jm500362j

Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. U

Full text of DOI:10.1021/jm500362j

Brief Article
pubs.acs.org/jmc
Structural Basis for Isoform Selectivity in a Class of Benzothiazole
Inhibitors of Phosphoinositide 3‑Kinase γ
§
‡
Philip N. Collier,* Gabriel Martinez-Botella, Mark Cornebise, Kevin M. Cottrell, John D. Doran,
James P. Griffith, Sudipta Mahajan, Francois Maltais, Cameron S. Moody, Emilie Porter Huck,
Tiansheng Wang, and Alex M. Aronov*
̧
Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, Massachusetts 02210, United States
S Supporting Information
*
ABSTRACT: Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to
potentially treat a range of disease states. Herein, we describe the evolution of a
reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective
benzothiazole inhibitors. Using X-ray crystallography, we discovered that
compound 22 occupies a previously unreported hydrophobic binding cleft
adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by
exploiting natural sequence differences among PI3K isoforms in this region.
hosphoinositide 3-kinases (PI3Ks), a family of enzymes
that act as lipid and protein kinases, have been linked to
numerous cellular functions including cell growth, differ-
Selective inhibition of PI3Kγ over the other PI3K isoforms
P
has proven to be a challenging endeavor, in part due to the high
sequence homology within the ATP binding site of the PI3Ks.
In this report, we describe a series of benzothiazole isoform-
selective inhibitors of PI3Kγ. Binding modes revealed from X-
ray crystallographic studies, combined with analysis of residue
differences among PI3K isoforms, shed light on some of the
selectivity determinants within the ATP binding site.
entiation, proliferation, survival, migration, and intracellular
1
−3
trafficking.
The eight known mammalian PI3Ks have been
divided into three classes based on their structure, regulatory
subunits, and substrate specificity. The most extensively studied
class I PI3Ks are heterodimeric complexes comprising a 110
kDa catalytic subunit and a smaller associated regulatory
subunit. Class Ia PI3Ks (α, β, and δ) containing the catalytic
subunits p110α, p110β, and p110δ, respectively, are activated
through tyrosine kinase signaling. In contrast, the sole class Ib
member, PI3Kγ, contains catalytic subunit p110γ associated
with either a p101 or p84 regulatory subunit, and is mostly
Upon analysis of the reported crystal structure of pan-PI3K
inhibitor PIK-93 (PI3Kγ K = 7 nM) in the active site of PI3Kγ,
i
we investigated the possibility of morphing from the phenyl-
thiazole core of PIK-93 to a benzothiazole, as depicted in 1
20
(Figure 1). We suspected that a 6-substituted benzothiazole
would better project into the deep ATP pocket, occupying
space adjacent to Tyr867 side chain. We were pleased to
observe submicromolar PI3Kγ affinity for 6-phenylbenzothia-
zole 2 (Table 1). Interestingly, a Novartis group has recently
reported identification of a similar benzothiazole scaffold from a
HTS campaign in their search for selective inhibitors of
4
activated through GPCRs.
While there is growing evidence that inhibitors of PI3Kγ may
have utility in treating cancer and cardiovascular disease, much
of the validation for PI3Kγ as a potential drug target has been
performed in the area of inflammation and autoimmune disease
because of its important role in such processes as lymphocyte
21
PI3Kα. We quickly discovered that replacement of the phenyl
group at C-6 of benzothiazole 2 with a 3-pyridyl substituent led
to a 20-fold improvement in PI3Kγ affinity (Table 1, 3). A
crystal structure of pyridine 3 in complex with PI3Kγ confirmed
the presence of two hydrogen bonds to the PI3Kγ hinge region,
specifically backbone amide nitrogen and backbone carbonyl of
Val882 within the ATP binding site (Figure 2a). The
interaction with Val882 is apparent in all known ligand-
3
,5−8
chemotaxis and mast cell degranulation.
The compelling
biology surrounding this target, with its potential for disease
modification, has attracted the attention of the pharmaceutical
industry. A number of selective inhibitors of PI3Kγ have now
4
,9−15
been published.
Whereas expression of PI3Kγ and PI3Kδ
is mainly confined to the hematopoietic system, the other PI3K
isoforms are ubiquitously expressed. If PI3Kγ is to be targeted
for a chronic indication, any cross-activity against the α and β
isoforms in particular should be avoided. It is known, for
example, that activation of class Ia PI3Ks is important in insulin
Special Issue: New Frontiers in Kinases
Received: March 7, 2014
1
6
signaling. PI3Kγ knockout mice are viable and show no
17−19
reproductive abnormalities.
©
XXXX American Chemical Society
A
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Journal of Medicinal Chemistry
Brief Article
Figure 1. X-ray crystal structure of reported pan-PI3K phenylthiazole
20
inhibitor PIK-93 bound to PI3Kγ (PDB code 2chz). Ample space is
available within the ATP binding site allowing for the possibility of a
ring fusion to benzothiazole core 1.
Figure 2. (a) X-ray structure of pyridine 3 bound to PI3Kγ (PDB code
4
PS7). Val882 forms a bidentate hinge-binding interaction with the
ligand. Water-mediated hydrogen bonds are formed from the pyridine
nitrogen atom to Tyr867 and Asp841. (b) X-ray structure of
dimethoxypyridine 10 bound to PI3Kγ (PDB code 4PS8). The
dimethoxy moiety coordinates Lys833.
22
Table 1. SAR at Benzothiazole C6 Position
pyridine ring (Table 1, 5). Electron-withdrawing groups at the
C5-position had a neutral effect on PI3Kγ affinity (Table 1, 7
and 8), while 4,5-dimethoxypyridine 10 was the highest affinity
compound of the set. This substitution pattern is consistent
with recent findings from Cellzome for a related triazolopyr-
11
idine scaffold. Overall, a remarkable gain in affinity (almost
00-fold) was realized on transitioning from phenyl analogue 2
8
to dimethoxypyridine analogue 10 as a result of forming three
favorable interactions to the ATP binding site of PI3Kγ.
Structural information collected for 10 in complex with
PI3Kγ indicated that the likely explanation for the increased
affinity of compounds possessing 5-alkoxy substituents was due
to a favorable hydrogen bonding interaction with the side chain
of catalytic lysine (Lys833) in PI3Kγ (Figure 2b).
As a result of SAR exploration in the region of the scaffold
occupied by the acetamide and replacement of the acetamide
with chain-extended ureas, we discovered compounds with
isoform selectivity, an observation subsequently reported in the
23,24
literature by other groups.
The urea functional group was
chosen, since it allowed rapid structure−activity profiling via
straightforward coupling reactions with amines (see Supporting
Information). Increasing the urea chain length resulted in
compounds with improved PI3Kγ affinity (Table 2, 17, 18 vs
14−16). However, we also made the serendipitous discovery
that increasing the chain length of trifluoroethylamide 17 by
one methylene unit, giving 18, dramatically improved selectivity
for PI3Kγ over PI3Kα by 72-fold while maintaining PI3Kγ
activity. We observed a similar selectivity trend in a small family
of alkylated imidazoles (19−22). Structural studies were
initiated in order to understand these observations.
bound structures of PI3Kγ. The dramatic improvement in
potency observed with pyridine 3 can be rationalized by the
observation of key water-mediated hydrogen bonds to Tyr867
and Asp841. These residues are conserved across PI3K
isoforms; increased activity against PI3Kγ (K = 39 nM) is
i
mirrored by increased activity against PI3Kα (K = 19 nM).
i
SARs at the benzothiazole C-6 position were further
22
explored, and the data are summarized in Table 1. A 10-
fold improvement in PI3Kγ affinity was obtained by
incorporating a methoxy group at the C-5 position on the
Propylimidazole 22, which was crystallized with PI3Kγ to a
resolution of 2.9 Å, adopted a U-shaped conformation with its
B
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Journal of Medicinal Chemistry
Brief Article
Table 2. Urea SAR and Corresponding PI3Kα Selectivity
Figure 3. X-ray structure of 22 bound to PI3Kγ (PDB code 4PS3).
Propylimidazole unit occupies a hydrophobic cleft adjacent to the ATP
binding site. Residue differences (Gly829 and Ala885) that drive
isoform selectivity are highlighted.
propyl group occupying a previously unreported binding cleft
adjacent to the ATP binding site (Figure 3). In the X-ray
structures of inhibitors 3 and 10 described earlier in this report,
hydrogen-bonding interactions are observed from Lys883 to
Thr827 (3.2 Å to side chain hydroxyl group of 10) and to
Glu814 (3.4 Å for 10). Similar interactions are observed in
Figure 4. Mechanistic hypothesis for isoform selectivity of ureas.
Hydrogen bonding interaction between Val882 and Ser885 (PI3Kγ
numbering) in PI3K class Ia isoforms bound to acetamide 5 is
eliminated in the case of urea binding (15 and 22). This disruption
sets up a negative interaction between free Ser885 hydroxyl group and
the hydrophobic urea side chain.
2
5,26
many of the reported ligand bound structures of PI3Kγ.
However, in the structure of 22 bound to PI3Kγ, neither of
these interactions of Lys883 are present; the pocket stitched up
by Lys883 interactions is open. Evidently, the energy cost of
this rearrangement is more than compensated by interactions
created by 22 in the newly formed binding cleft.
PI3K isoform sequence on the periphery of the ATP binding
site is divergent, in contrast to the conservation of residues
within the ATP binding site. By comparison of amino acid
residues within and surrounding this newly identified binding
cleft, an explanation for the observed selectivities of the urea
analogues was proposed. A degree of selectivity over all PI3K
class Ia isoforms is imparted by a functional group change from
amide to urea (Figure 4, 5 vs 15 and 22). In a published X-ray
structure of PI3Kδ, a 2.9 Å hydrogen bond is present between
ATP binding site residue Val828 (corresponding residue in
class Ia PI3Ks and is disrupted upon urea binding (Figure 4).
The urea forms a bidentate interaction with the backbone
carbonyl of Val882, liberating the Ser885 hydroxyl group, which
negatively interacts with the lipophilic side chain of the ureas.
No such negative interaction exists on urea binding to PI3Kγ
where residue 885 is alanine.
Further improvement in PI3Kα selectivity of the ureas was
realized with increasing chain length. This can be explained by a
key residue difference inside the newly described selectivity
pocket: an unfavorable interaction of the propyl group of 22
with an Asp residue in PI3Kα (Gly829 in PI3Kγ). Protrusion
into the hydrophobic pocket has little effect on PI3Kγ
27
PI3Kγ is numbered Val882) and Ser831. We hypothesize that
this internal hydrogen bonding interaction is conserved across
C
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Journal of Medicinal Chemistry
Brief Article
selectivity over the β and δ isoforms (Figure 4, 15 vs 22),
consistent with our hypothesis. The 200-fold PI3Kα selectivity
seen with phenoxyethylamide 24 (Table 2) again is consistent
with a detrimental interaction of the phenyl group of 24 with
the Asp residue of PI3Kα. A striking combination of the two
aforementioned effects accounts for the dramatic PI3Kα
selectivity difference observed between 17 and homologue
an essential amplifier of mast cell function. Immunity 2002, 16, 441−
4
51.
(6) Ghigo, A.; Damilano, F.; Braccini, L.; Hirsch, E. PI3K inhibition
in inflammation: toward tailored therapies for specific diseases.
BioEssays 2010, 32, 185−196.
(7) Siragusa, M.; Katare, R.; Meloni, M.; Damilano, F.; Hirsch, E.;
Emanueli, C.; Madeddu, P. Involvement of phosphoinositide 3-kinase
γ in angiogenesis and healing of experimental myocardial infarction in
mice. Circ. Res. 2010, 106, 757−768.
1
8. Presumably, the amide carbonyl group of 17 makes a
positive interaction with the liberated Ser885 side chain of
PI3Kα while the clash between the shorter side chain of 17 and
Asp829 of PI3Kα is reduced.
(8) Seropian, I. M.; Abbate, A.; Toldo, S.; Harrington, J.; Smithson,
L.; Ockaili, R.; Mezzaroma, E.; Damilano, F.; Hirsch, E.; Van Tassell,
B. W. Pharmacological inhibition of phosphoinositide 3-kinase gamma
(PI3Kγ) promotes infarct resorption and prevents adverse cardiac
remodeling after myocardial infarction in mice. J. Cardiovasc.
Pharmacol. 2010, 56, 651−658.
In summary, we have discovered potent and isoform selective
inhibitors of PI3Kγ based around a benzothiazole core. To our
knowledge, this is the first report that details structural
determinants of PI3Kγ selectivity around a newly defined
binding cleft adjacent to the ATP binding site and provides a
framework to examine PI3K isoform selectivity.
(
9) Pomel, V.; Klicic, J.; Covini, D.; Church, D. D.; Shaw, J. P.;
Roulin, K.; Burgat-Charvillon, F.; Valognes, D.; Camps, M.; Chabert,
C.; Gillieron, C.; Francon, B.; Perrin, D.; Leroy, D.; Gretener, D.;
Nichols, A.; Vitte, P. A.; Carboni, S.; Rommel, C.; Schwarz, M. K.;
Ruckle, T. Furan-2-ylmethylene thiazolidinediones as novel, potent,
and selective inhibitors of phosphoinositide 3-kinase γ. J. Med. Chem.
006, 55, 3857−3871.
10) Cushing, T. D.; Metz, D. P.; Whittington, D. A.; McGee, L. R.
̧
̈
ASSOCIATED CONTENT
Supporting Information
■
S
2
(
*
Synthetic schemes and experimental procedures, character-
izaton of organic molecules, biochemical assays, crystallographic
information. This material is available free of charge via the
Internet at http://pubs.acs.org.
PI3Kδ and PI3Kγ as targets for autoimmune and inflammatory
diseases. J. Med. Chem. 2012, 55, 8559−8581.
(11) Bell, K.; Sunose, M.; Ellard, K.; Cansfield, A.; Taylor, J.; Miller,
W.; Ramsden, N.; Bergami, G.; Neubauer, G. SAR studies around a
series of triazolopyridines as potent and selective PI3Kγ inhibitors.
Bioorg. Med. Chem. Lett. 2012, 22, 5257−5263.
AUTHOR INFORMATION
Corresponding Authors
P.N.C.: phone, 1-617-341-6921; e-mail, philip_collier@vrtx.
com.
■
*
(12) Oka, Y.; Yabuuchi, T.; Fujii, Y.; Ohtake, H.; Wakahara, S.;
Matsumoto, K.; Endo, M.; Tamura, Y.; Sekiguchi, Y. Discovery and
optimization of a series of 2-aminothiazole-oxazoles as potent
phosphoinositide 3-kinase γ inhibitors. Bioorg. Med. Chem. Lett.
*
A.M.A.: phone, 1-617-341-6804; e-mail, alex_aronov@vrtx.
com.
2
(
012, 22, 7534−7538.
13) Oka, Y.; Yabuuchi, T.; Oi, T.; Kuroda, S.; Fujii, Y.; Ohtake, H.;
Present Addresses
M.C.: AstraZeneca R&D Boston, 35 Gatehouse Drive,
Inoue, T.; Wakahara, S.; Kimura, K.; Fujita, K.; Endo, M.; Taguchi, K.;
Sekiguchi, Y. Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-
oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914)
as an orally potent phosphoinositide 3-kinase γ inhibitor for the
treatment of inflammatory dieases. Bioorg. Med. Chem. 2013, 21,
‡
Waltham, Massachusetts 02451, United States.
§
G.M.-B.: Sage Therapeutics, 215 First Street, Cambridge,
Massachusetts 02142, United States.
7
(
578−7583.
Notes
14) Leahy, J. W.; Buhr, C. A.; Johnson, H. W. B.; Gyu Kim, B.; Baik,
The authors declare no competing financial interest.
T.; Cannoy, J.; Forsyth, T. P.; Jeong, J. W.; Lee, M. S.; Ma, S.; Noson,
K.; Wang, L.; Williams, M.; Nuss, J. M.; Brooks, E.; Foster, P.; Goon,
L.; Heald, N.; Holst, C.; Jaeger, C.; Lam, S.; Lougheed, J.; Nguyen, L.;
Plonowski, A.; Song, J.; Stout, T.; Wu, X.; Yakes, M. F.; Yu, P.; Zhang,
W.; Lamb, P.; Raeber, O. Dicovery of a novel series of potent and
orally bioavailable phosphoinositide 3-kinase γ inhibitors. J. Med.
Chem. 2012, 55, 5467−5482.
(15) Sunose, M.; Bell, K.; Ellard, K.; Bergamini, G.; Neubauer, G.;
Werner, T.; Ramsden, N. Discovery of 5-(2-amino-[1,2,4]triazolo[1,5-
a]pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide (CZC24758), as
a potent, orally bioavailable and selective inhibitor of PI3K for the
treatment of inflammatory disease. Bioorg. Med. Chem. Lett. 2012, 22,
ACKNOWLEDGMENTS
■
The authors thank Drs. M. Clark, J. Green, and J. Empfield for
helpful comments during the preparation of this manuscript
and Dr. B. Davis for high resolution mass spectrometric
assistance.
ABBREVIATIONS USED
■
GPCR, G-protein-coupled receptor
4
(
613−4618.
REFERENCES
16) Ueki, K.; Yballe, C. M.; Brachmann, S. M.; Vicent, D.; Watt, J.
■
(
1) Vanhaesebroeck, B.; Guillermet-Guibert, J.; Graupera, M.;
M.; Kahn, C. R.; Cantley, L. C. Increased insulin sensitivity in mice
lacking p85β subunit of phosphoinositide 3-kinase. Proc. Natl. Acad.
Sci. U.S.A. 2002, 99, 419−424.
(17) Hirsch, E.; Katanaev, V. L.; Garlanda, C.; Azzolino, O.; Pirola,
L.; Silengo, L.; Sozzani, S.; Mantovani, A.; Altruda, F.; Wymann, M. P.
Central role for G protein-coupled phosphoinositide 3-kinase γ in
inflammation. Science 2000, 287, 1049−1053.
(18) Li, Z.; Jiang, H.; Xie, W.; Zhang, Z.; Smrcka, A. V.; Wu, D. Roles
of PLC-β2 and -β3 and PI3Kγ in chemoattractant-mediated signal
transduction. Science 2000, 287, 1046−1049.
(19) Sasaki, T.; Irie-Sasaki, J.; Jones, R. G.; Oliveira-dos-Santos, A. J.;
Stanford, W. L.; Bolon, B.; Wakeham, A.; Itie, A.; Bouchard, D.;
Kozieradzki, I.; Joza, N.; Mak, T. W.; Ohashi, P. S.; Suzuki, A.;
Bilanges, B. The emerging mechanisms of isoform-specific PI3K
signalling. Nat. Rev. Mol. Cell Biol. 2010, 11, 329−342.
(
2) Cantley, L. C. The phosphoinositide 3-kinase pathway. Science
2
(
002, 296, 1655−1657.
3) Hawkins, P. T.; Anderson, K. E.; Davidson, K.; Stephens, L. R.
Signalling through class 1 PI3Ks in mammalian cells. Biochem. Soc.
Trans. 2006, 34, 647−662.
(
4) Ameriks, M. K.; Venable, J. D. Small molecule Inhibitors of
phosphoinositide 3-kinase (PI3K) δ and γ. Curr. Top. Med. Chem.
009, 9, 738−753.
5) Laffargue, M.; Calvez, R.; Finan, P.; Trifilieff, A.; Barbier, M.;
Altruda, F.; Hirsch, E.; Wymann, M. P. Phosphoinositide 3-kinase γ is
2
(
D
dx.doi.org/10.1021/jm500362j | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Brief Article
Penninger, J. F. Function of PI3Kγ in thymocyte development, T cell
activation, and neutrophil migration. Science 2000, 287, 1040−1046.
(
20) Knight, Z. A.; Gonzalez, B.; Feldman, M. E.; Zunder, E. R.;
Goldenberg, D. D.; Williams, O.; Loewith, R.; Stokoe, D.; Balla, A.;
Toth, B.; Balla, T.; Weiss, W. A.; Williams, R. L.; Shokat, K. M. A
pharmacological map of the PI3-K family defines a role for p110α in
insulin signaling. Cell 2006, 125, 733−747.
(
21) Pecchi, S.; Ni, Z.-J.; Han, W.; Smith, A.; Lan, J.; Burger, M.;
Merritt, H.; Wiesmann, M.; Chan, J.; Kaufman, S.; Knapp, M. S.;
Janssen, J.; Huh, K.; Voliva, C. F. Structure guided optimization of a
fragment hit to imidazopyridine inhibitors of PI3K. Bioorg. Med. Chem.
Lett. 2013, 23, 4652−4656.
(
22) Some of these compounds have previously been reported: 2
(
WO 2010008847 A2); 3 (ref 21, WO 201000144 A1, and WO
2
2
010008847 A2); 5, 6, and 19 (WO 201000144 A1); 7 and 9 (WO
009017822 A2); 12 (ref 21). See Supporting Information for full
bibliographic information.
23) Bruce, I.; Akhlaq, M.; Bloomfield, G. C.; Budd, E.; Cox, B.;
(
Cuenoud, B.; Finan, P.; Gedek, P.; Hatto, J.; Hayler, J. F.; Head, D.;
Keller, T.; Kirman, L.; Leblanc, C.; Le Grand, D.; McCarthy, C.;
O’Connor, D.; Owen, C.; Oza, M. S.; Pilgrim, G.; Press, N. E.;
Sviridenko, L.; Whitehead, L. Development of isoform selective PI3-
kinase inhibitors as pharmacological tools for elucidating the PI3K
pathway. Bioorg. Med. Chem. Lett. 2012, 22, 5445−5450.
(
24) Ellard, K.; Sunose, M.; Bell, K.; Ramsden, N.; Bergamini, G.;
Neubauer, G. Discovery of novel PI3Kγ/δ inhibitors as potential
agents for inflammation. Bioorg. Med. Chem. Lett. 2012, 22, 4546−
4
549.
(
25) Berndt, A.; Miller, S.; Williams, O.; Le, D. D.; Houseman, B. T.;
Pacold, J. I.; Gorrec, F.; Hon, W. C.; Liu, Y.; Rommel, C.; Gaillard, P.;
Ruckle, T.; Schwarz, M. K.; Shokat, K. M.; Shaw, J. P.; Williams, R. L.
̈
The p110 delta structure: mechanisms for selectivity and potency of
new PI(3)K inhibitors. Nat. Chem. Biol. 2010, 6, 117−124.
(
̈
26) Camps, M.; Ruckle, T.; Ji, H.; Ardissone, V.; Rintelen, F.; Shaw,
J.; Ferrandi, C.; Chabert, C.; Gillieron, C.; Franc o̧ n, B.; Martin, T.;
Gretener, D.; Perrin, D.; Leroy, D.; Vitte, P.-A.; Hirsch, E.; Wymann,
M. P.; Cirillo, R.; Schwarz, M. K.; Rommel, C. Blockade of PI3Kγ
suppresses joint inflammation and damage in mouse models of
rheumatoid arthritis. Nat. Med. 2005, 11, 936−943.
(
27) Zask, A.; Verheijen, J. C.; Curran, K.; Kaplan, J.; Richard, D. J.;
Nowak, P.; Malwitz, D. J.; Brooijmans, N.; Bard, J.; Svenson, K.; Lucas,
J.; Toral-Barza, L.; Zhang, W.-G.; Hollander, I.; Gibbons, J. J.;
Abraham, R. T.; Ayral-Kaloustian, S.; Mansour, T. S.; Yu, K. ATP-
competitive inhibitors of the mammalian target of rapamycin: design
and synthesis of highly potent and selective pyrazolopyrimidines. J.
Med. Chem. 2009, 52, 5013−5016.
E
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