Targeting an EGFR Water Network with 4-Anilinoquin(az)oline Inhibitors for Chordoma

Article abstract of DOI:10.1002/cmdc.201900428

Quinoline- and quinazoline-based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non-small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe severa

Full text of DOI:10.1002/cmdc.201900428

Accepted Article
Title: Targeting an EGFR water network using novel 4-
anilinoquin(az)olines inhibitors for chordoma
Authors: Christopher Robert Michael Asquith, Kaitlyn Ann Maffuid,
Tuomo Laitinen, Chad Torrice, Graham J. Tizzard, Daniel J.
Crona, and William J. Zuercher
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To be cited as: ChemMedChem 10.1002/cmdc.201900428
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10.1002/cmdc.201900428
ChemMedChem
COMMUNICATION
Targeting an EGFR water network using novel 4-
anilinoquin(az)olines inhibitors for chordoma
Christopher R. M. Asquith,[a,b]* Kaitlyn A. Maffuid,[c] Tuomo Laitinen,[d] Chad D. Torrice,[c] Graham
J. Tizzard,[e] Daniel J. Crona,[c,f] William J. Zuercher[b,f]
*
Abstract: Quinoline- and quinazoline-based kinase inhibitors of the
epidermal growth factor receptor (EGFR) have been used to target
non-small cell lung cancer (NSCLC) and chordomas with varying
amounts of success. We designed and prepared compounds to probe
several key structural features including an interaction with Asp855
within the EGFR DGF motif and interactions with the active site water
network. EGFR target engagement was then evaluated in a cellular
assay, with the inhibitors then profiled in representative cellular
models of NSCLC and chordomas. In addition to a structure activity
relationship insight for EGFR inhibitor design with potent dimethoxy
quin(az)oline identified (1, 4 & 7). We also found a compound (18) that
is the most potent inhibitor (IC50 = 310 nM) on the UCH-2 chordoma
cell line to date.
Cancer is the second leading cause of death globally, and was
responsible for an estimated 9.6 million deaths in 2018.1 Kinases
have been successfully utilized as drug targets for the past 30
years, with 49 kinase inhibitors approved by the FDA to date,
mainly for cancer indications.2 One target that has been intensely
studied is epidermal growth factor receptor (EGFR). EGFR
inhibitors including gefitinib and erlotinib provide significant
clinical benefit in patients diagnosed with non-small cell lung
cancer (NSCLC), while lapatinib was developed as a dual EGFR
and HER2 inhibitor for the treatment of HER2-positive breast
cancers (Figure 1).3-5
Figure 1. Example structures of clinical EGFR quinazolines.
Therapeutic intervention in the EGFR pathway is not limited to
NSCLC and breast cancer, along with a number of other cancers
showing sensitivity to EGFR inhibitors.6 These include chordomas,
Kinase inhibitors commonly have off-targets across the
kinome that confound the ability to accurately define the
mechanism of action that cause induction of phenotypes of
interest.14 The 4-anilino-quinoline and 4-anilino-quinazoline
scaffolds have demonstrated a range of activity profiles across
the kinome from highly selective to broadly promiscuous.15-17 One
recurring off-target of these scaffolds is cyclin G-associated
kinase (GAK), which is frequently observed to bind 4-anilino-
quinoline, quinazolines and 3-cyano-quinolines.17 One example of
a narrow spectrum kinome profile quinazoline is lapatinib, with
only a handful of off-targets in addition to EGFR, HER2 and no
GAK binding.17
which are rare tumors that arise along the bones of the central
nervous system and spine.7 These tumors are a significant
challenge to treat, and surgical resection is the current preferred
course of treatment.7-8 EGFR and its ligand EGF are highly
expressed in chordomas, and copy number gains of EGFR occur
in 40 % of chordomas. A number of EGFR inhibitors have been
identified that are active in cellular models of chordoma, with
afatinib currently in phase 2 clinical trials for the treatment of
chordoma (Figure 1).9-13
We docked lapatinib into the ATP binding site of EGFR and
observed that the aniline portion was able to access a deeper
lipophilic pocket, displacing 2 water molecules in the process
(Figure 2A).18-19 Inhibitors lacking an extended head-group were
not able to access this pocket, including derivatives of erlotinib
(Figure 2B-D). The methoxy groups also appeared to play an
important role in binding by displacement of two additional water
molecules at the solvent-exposed ATP binding site (Figure 2C)
(PDB: 1XKK).5 Employing the Schrödinger Maestro suite allowed
us to explore the EGFR ATP-binding site properties with the 4-
anilino-quin(az)oline scaffold (Figure 2D).20
[a]
[b]
Dr. C. R. M. Asquith
Department of Pharmacology, School of Medicine, University of
North Carolina at Chapel Hill, NC 27599, (USA)
E-mail: chris.asquith@unc.edu
Dr. C. R. M. Asquith, Prof. William J. Zuercher
Structural Genomics Consortium, UNC Eshelman School of
Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill,
NC 27599, (USA)
E-mail: william.zuercher@unc.edu
[c]
Kaitlyn A. Maffuid, C. D. Torrice, Prof. D. J. Crona
Division of Pharmacotherapy and Experimental Therapeutics, UNC
Eshelman School of Pharmacy, University of North Carolina at
Chapel Hill, Chapel Hill, NC 27599, (USA)
Prof. T. Laitinen
Interested to explore these effects further, we designed and
prepared several focused arrays of compounds to probe the
structure activity relationships of the quinoline/quinazoline series.
We synthesized a series of compounds (1-9) through nucleophilic
[d]
[e]
[f]
School of Pharmacy, Faculty of Health Sciences, University of
aromatic displacement of commercially
available 4-
Eastern Finland, 70211 Kuopio, (Finland)
Dr. Graham J. Tizzard
chloroquin(az)olines in good yields (56-69 %), consistent with
previous reports (Scheme 1).13, 15-16, 21
School of Chemistry, University of Southampton, Southampton,
SO17 1BJ, (United Kingdom)
Prof. D. J. Crona, Prof. William J. Zuercher
Lineberger Comprehensive Cancer Center, University of North
Carolina at Chapel Hill, Chapel Hill, NC 27599, (USA)
1
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10.1002/cmdc.201900428
ChemMedChem
COMMUNICATION
Figure 2. Examples of docked compounds in the EGFR ATP-binding domain (PDB: 1XKK). Red balls (A and C) are simulated waters with the ATP binding site.
with respect to 1. This structural modification also led to a loss of
in cellular potency in both A431 and UCH-1 cell lines. In contrast,
its potency in UCH-2 cells increased by more than 2-fold.
However, the potency values of 2 and 3 were still in the low double
digit micromolar range in UCH2 cells.
The switch from quinoline to quinazoline (4) showed a similar
potency range to 1, with slightly stronger potency in A431 cells.
The removal of either methoxy (5-6) had no impact on cellular
EGFR activity, but did reduce activity in all 3 cancer cell lines, with
no effect in WS1 cells. The 3-cyano quinoline hinge binder
showed a marked drop off EGFR activity in cells. The 6,7-
dimethoxy analog (7) showed similar potencies to the mono-
methoxy quinazolines 5 and 6. It was then surprising, that the
removal of either methoxy (8 and 9) reduced the anti-proliferative
effect seen in 7; given that the EGFR cellular activity was near
equipotent. This effect is likely due to the involvement of other
targets or could be a kinetic effect of the compounds.
Scheme 1. General synthetic procedure
These compounds were profiled in an EGFR cellular activity
assay, two patient-derived chordoma cell lines (UCH-1 and UCH-
2), a lung cancer cell line (A431), and a normal skin fibroblast line
(WS1) (Table 1 & 2). The 6,7-dimethoxyquinolin-4-amine with the
erlotinib 3-ethynylaniline (1) showed high potency in the cell-
based EGFR phosphorylation assay (IC50 = 270 nM), as
previously reported.13 The data from the two chordoma cell lines
is also consistent with previous reports.13 The A431 cells showed
moderate activity at IC50 = 1.4 µM and 3-fold weaker potency on
WS1 normal fibroblast cell viability. The removal of either methoxy
group to form the 6-methoxy (2) or 7-methoxy (3) yielded
compounds with more than a 60-fold drop in EGFR in cell potency,
With the results of the small focused series in hand, we then
modified the aniline scaffold, with the aim of establishing an
Table 1. Results of a small series of compounds with varied hinge binding moieties (1-9).
EGFRa
A431
UCH-1
UCH-2
WS1
Cmpd
R1
R2
X
IC50 (µM)
IC50 (µM)b
1
2
3
4
5
6
7
8
9
OMe
OMe
H
OMe
H
CH
CH
0.27c
1.4
10
0.54
6.6
42
16
4.6
16
>100
>100
15
OMe
OMe
H
CH
>20
0.55c
0.59
0.53
1.8c
3.5
3.4
0.85
2.2
8
9.4
17
OMe
OMe
H
N
0.63
1.4
66
N
47
>100
>100
>100
>100
>100
OMe
OMe
H
N
1.9
1.2
36
OMe
OMe
H
C-CN
C-CN
C-CN
1.7
>100
44
4.1
19.6
4.1
>100
40
OMe
1.1
aProQinase In-cell assay (n=1), b(n=3) standard error of the means are all within 10%, cLiterature data reference 13
2
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10.1002/cmdc.201900428
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COMMUNICATION
Scheme 2. Synthetic procedure for 13-15 and 17
Scheme 3. Synthetic procedure for 16
The 6,7-dimethoxyquinolin-4-amine with the lapatinib-derived
hydroxy amide aniline (13) showed double digit micromolar
potency in the cellular EGFR phosphorylation assay, moderate
activity in A431 cells, and higher potency in UCH-1 and UCH-2
cells. Removal of either of the methoxy groups (14 and 15) led to
an increase in activity in the chordoma cell lines with no change
in their anti-proliferative effect within A431 cells. The activity
profiles of 14 and 15 diverged from the results of monomethoxy
compounds in the previous compound set (1-9).
internal hydrogen bond, not only to form a pre-organized structure
but also to engage in an interaction with Asp855 (Figure 3).
Interestingly, our hypothesis of including the alcohol on the
head-group proved to be pivotal for activity: removal of the alcohol
(16) led to diminished activity compared with activity previously
observed in 13-15. We also incorporated a tert-butyl group on the
pendant benzyl (17) to more fully occupy the displaced water
pocket. This modification only led to additional molecular weight,
with no potency gain compared with 13. It was surprising that the
para-methyl benzylic ether substitution (18) with no alcohol
showed no EGFR activity in cells and a limited effect in A431 cells.
However, in the two chordoma cell lines there was a sharp
increase in activity. 18 is one of the most potent compounds seen
to date with IC50 = 330 nM and 310 nM for UCH-1 and UCH-2,
respectively. This result is more impressive considering that UCH-
2 is typically less sensitive to compound treatment.11 However, 18
does show some toxicity in WS1 (IC50 = 1.1 µM). Removal of the
benzyl in 19 had a similar effect to removing the alcohol in 16 with
most activity lost, but moderate potency in A431 was still
observed (Table 2).
Figure 3. Docking of 15 into EGFR
In tandem, we looked at the water network in EGFR (Figure 4)
and found that adding a methyl group to the pendent benzyl had
the potential to increase potency by displacing a deep pocket
water molecule.
We examined compounds 13-19 in four additional primary
chordoma cell lines and found subsets of compounds with similar
activity (Table 3). 13-15 showed broadly similar activities between
IC50 = 1-3 µM, and 14 was slightly weaker on UCH-12 at IC50
=
9.3 µM. The removal of the alcohol (16) resulted in a loss of all
anti-proliferative effects across all 4 cell lines (IC50 >10 µM).
Compound 17 had activities similar to 13-15, but the lack of
activity on UCH-2 (IC50 > 100 µM), is even more surprising given
these results. 18 was still the standout compound with the only
submicromolar potency across these 4 additional cell lines (UCH-
12 IC50 = 800 nM; Table 3). The selectivity index was equivalent
to lapatinib, but the activity profile was >10-fold in all and >100-
fold in some cell lines. Removal of the benzyl (19) had a
significant effect on EGFR activity in the 4 additional cell lines,
with limited anti-proliferative effects (IC50 >10 µM) and an increase
in toxicity in WS1 cells.
Figure 4. Docking pose of compound 15 superimposed with WaterMap
simulation of EGFR (PDB:1XKK) showing displacement of high energy water.
We prepared several additional compounds (13-18) following a
three-step protocol from commercially available 2-amino-5-
nitrophenol (10) as a starting material. 10 was coupled with CDI
to furnish an amide bond, followed by H2 reduction to give
intermediates 11 and 12 (Scheme 2). SNAr reactions of
intermediates 11 and 12 under reflux provided compounds 13-15
and 17 in excellent yields (58-85%).15,17 The des-hydroxy
compound (16) proved inaccessible via a nucleophilic aromatic
displacement (even up to 150 °C, DMF, DIPEA, 18 h), and
required Buchwald-Hartwig conditions (Scheme 3) to afford 16 in
good overall yield (72 %).15
3
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10.1002/cmdc.201900428
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COMMUNICATION
Table 2. Matched pair comparison of benzyloxyanilines
EGFRa
A431
UCH-1
UCH-2
WS1
Compound
R1
R2
R3
R4
IC50 (µM)
IC50 (µM)b
13
14
15
16
17
18
19
OMe
OMe
H
OMe
H
OH
OH
OH
H
A
A
A
A
B
C
D
14
14
1.6
1.8
1.7
21
1.6
0.93
0.49
14
2.4
1.4
1.4
1.4
OMe
OMe
OMe
OMe
OMe
6.3
>20
13
0.68
21
0.86
>100
1.9
OMe
OMe
OMe
OMe
OH
H
1.8
1.5
3.4
1.2
>100
0.31
15
>20
>20
0.33
15
1.1
H
3.8
aProQinase In-cell assay (n=1), b(n=3) standard error of the means are all within 10%
We then solved a small molecule crystal structure of 13 in
order to explore the conformation of the aniline portion of the
molecule and to directly observe the potential internal hydrogen
bond between the carbonyl of the amide and the phenolic alcohol.
The small molecule crystal structure of 13 was solved as a
monoclinic structure with a 27:73 ratio favoring a species without
pre-organization to the internal seven membered ring system
(Figure 5).22 Under our crystallisation conditions the phenolic
alcohol also formed a 2.98 Å hydrogen bond with the chloride ion.
significant electrostatic component within the lattice acting as an
anchor, hindering further pre-organisation. The rigidity imparted
by the alcohol onto the pendant arm structure could be leading to
the improved potency seen on EGFR with 13 and not observed
with 16.
EGFR inhibitors have been used to target NSCLC, pancreatic
cancer, breast cancer, and now chordomas. There is variation in
efficacy across inhibitors, with the emergence of secondary
resistance to these inhibitors known clinically particularly in the
case of NSCLC.23 We have highlighted a series of modifications,
investigating the effect of key structural features and the water
network of EGFR on the quin(az)oline scaffold. These
modifications can be used to enhance or reduce EGFR activity,
and generally have a pronounced effect on cellular potency.
The sensitivity of the kinase ATP water network, while
relatively under explored, offers an exciting opportunity to
increase potency and potentially increase selectivity.18-19 One of
the key results observed was that removal of one the methoxy
groups of 1 led to a significant loss of cellular EGFR potency and
anti-proliferative effects. Interestingly, this loss of potency is not
observed in the other quinazoline and 3-cyanoquinoline templates,
likely due to the orientation of the hinge binder and aniline at a
more acute angle in the EGFR ATP binding site (Figure 2). This
was less significant when looking at the extended aniline structure
27
:
73
Figure 5. Small molecules crystal structure of 13
While we would expect the predominant from to be the
internally H-bonded structure, with chloride present there is a
Table 3. Investigation of across four patient-derived chordoma cell lines
UCH-1
UCH-2
CH-22
UM-Chor1
IC50 (µM)a
UCH-12
UCH-7
WS1
Cmpd
Erlotinibb
8.6
23
5.1
1.4
3.2
1.6
0.93
0.49
14
18
23
>50
>50
25
>50
>50
25
>10
>50
33
>50
>50
26
Gefitinibb
Lapatinibb
>50
2.4
13
13
14
15
16
17
18
19
1.9
1.6
1.7
52
1.5
2.6
1.7
36
1.3
9.3
1.9
73
1.7
1.9
1.7
10
1.4
1.4
1.4
0.86
>100
1.9
0.68
21
1.2
0.33
15
>100
0.31
15
1.7
5.8
12
1.5
4.0
21
2.4
0.80
39
1.9
11
1.1
35
3.8
a(n=3) standard error of the means are all within 10%, bLiterature data reference 13
4
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10.1002/cmdc.201900428
ChemMedChem
COMMUNICATION
of 13-16 where the alcohol interaction with Asp855 and
conformational rigidity were more significant.24 The benzyl
substitution had an enhanced anti-proliferative effect on
chordoma cell line, consistent with the involvement of EGFR as a
target for these compounds. This result supports the earlier
observation that, despite not being involved in the key hinge
binding interactions, the benzyl had a pronounced effect on EGFR
activity, likely due to displacement of EGFR active site water
molecules.
were analyzed within 6 Å from the docked ligand, and the 2 nS
simulation was conducted with OPLS3e force field.
Chemistry
General procedure for the synthesis of 4-anilinoquin(az)olines:
4-chloroquin(az)oline derivative (1.0 eq.), aniline derivative (1.1
eq.), and iPr2NEt (2.5 eq.) were suspended in ethanol (10 mL) and
refluxed for 18 h. The crude mixture was purified by flash
chromatography using EtOAc:hexane followed by 1-5
%
methanol in EtOAc; After solvent removal under reduced pressure,
the product was obtained as a free flowing solid or recrystallized
from ethanol/water.
Conclusions
In summary, two distinct focused series of 4-
anilinoquin(az)olines have been identified that interact with the
EGFR ATP-binding site water network. The dimethoxy
substitution (1, 4 & 7) was shown to have a synergistic effect
between the methoxy groups likely due to the occupation of two
water binding sites. The second series (13-17) utilised
conformational rigidity and access to the deeper hydrophobic with
the EGFR lipophilic pocket of the ATP binding site. We
demonstrated that the alcohol is able to make an interaction both
internally and with a key Asp855 (D855) residue within EGFR.
We also identified a potent inhibitor with an acceptable
therapeutic window (18) of both the A431 NSCLC cells and
chordoma cell lines. Benchmarked against literature EGFR
inhibitors, 18 has a greater than 10-fold (and in some cases >100-
fold) anti-proliferative potency against all chordoma cell lines, with
no increase in toxicity profile compared to the representative
clinical EGFR inhibitors lapatinib and erlotinib. Chordomas, in
particular, are difficult to treat, and 18 along with the other 4-
N-(3-Ethynylphenyl)-6,7-dimethoxyquinolin-4-amine (1): light-
beige solid (67%, 228 mg, 0.749 mmol) MP 232-234 oC; 1H NMR
(400 MHz, DMSO-d6) δ = 10.94 (s, 1H), 8.35 (d, J=6.9 Hz, 1H),
8.25 (s, 1H), 7.60 (q, J= 1.4 Hz, 1H), 7.58–7.52 (m, 2H), 7.51–
7.43 (m, 2H), 6.76 (d, J=6.9 Hz, 1H), 4.34 (s, 1H), 3.99 ppm (d,
J=19.4 Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ =154.6, 152.9,
149.4, 139.8, 138.1, 135.3, 130.2, 130.0, 128.1, 125.9, 123.2,
111.9, 103.0, 99.7, 99.31, 82.6, 81.9, 56.9, 56.1. HRMS-ESI
(m/z): [M+H]+ calcd for C19H16N2O2 305.1290, found 305.1278;
LC: tR = 3.75 min, purity > 98%. consistent with previous reports.15
N-(3-Ethynylphenyl)-6-methoxyquinolin-4-amine (2) yellow
solid (67 %, 237 mg, 0.865 mmol) MP 195-197 oC; 1H NMR (400
MHz, DMSO-d6) δ 11.06 (s, 1H), 8.43 (d, J = 6.8 Hz, 1H), 8.32 (d,
J = 2.6 Hz, 1H), 8.06 (d, J = 9.3 Hz, 1H), 7.66 (dd, J = 9.2, 2.6 Hz,
1H), 7.62 (q, J = 1.4 Hz, 1H), 7.59 – 7.54 (m, 2H), 7.54 – 7.47 (m,
1H), 6.83 (d, J = 6.8 Hz, 1H), 4.34 (s, 1H), 4.00 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 158.0, 153.7, 140.6, 137.9, 133.5, 130.3,
130.3, 128.3, 126.0, 125.5, 123.2, 121.9, 118.6, 103.1, 99.8, 82.6,
82.0, 56.6. HRMS m/z [M+H]+ calcd for C18H15N2O: 275.1184
found = 275.1175; LC tR = 4.46 min, >98% Purity.
anilinoquin(az)oline series members could yield
candidate with an improved cellular potency and toxicity profile.
a clinical
Experimental Section
Modelling method
N-(3-Ethynylphenyl)-7-methoxyquinolin-4-amine (3) mustard
solid (69 %, 244 mg, 0.891 mmol) MP 282-284 oC; 1H NMR (400
MHz, DMSO-d6) δ 11.06 (s, 1H), 8.81 (d, J = 9.4 Hz, 1H), 8.42 (d,
J = 7.0 Hz, 1H), 7.62 – 7.57 (m, 1H), 7.57 – 7.52 (m, 2H), 7.52 –
7.43 (m, 2H), 7.40 (dd, J = 9.3, 2.5 Hz, 1H), 6.72 (d, J = 7.0 Hz,
1H), 4.34 (s, 1H), 3.96 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
163.0, 154.3, 142.3, 140.7, 137.8, 130.3 (s, 2C), 128.3, 126.1,
125.8, 123.2, 118.2, 111.6, 99.9, 99.3, 82.6, 82.0, 56.0. HRMS
m/z [M+H]+ calcd for C18H15N2O: 275.1184 found = 275.1175; LC
tR = 4.44 min, >98% Purity.
Molecular modelling was performed using Schrödinger
Maestro software package (Small-Molecule Drug Discovery Suite
2018-4, Schrödinger, LLC, New York, NY, 2018) Prior to docking
simulations structures of small molecules were prepared using
and the LigPrep module of Schrodinger suite employing OPLS3e
force field.25 In the case of human EGFR there are numerous PDB
structures available representing various ligand binding
conformations, showing flexibility in the position of so-called the
C-helix. Suitable docking templates were searched using LPDB
module of Schrödinger package and carrying out visual inspection
of available experimental structures with assistance of LiteMol
plug-in available at website of UniProt database. Selected
coordinates (PDB:3W2S) have been co-crystallized with at
resolution of 1.9 Å with a small molecule inhibitor.5 The PDB
structure of EGFR was H-bond optimized and minimized using
standard protein preparation procedure of Schrödinger suite. The
ligand docking was performed using SP settings of Schrodinger
docking protocol with softened vdw potential (scaling 0.6), except
for 7 where induced fit docking protocol was used employing
standard settings. In order to improve convergence of docking
poses a hydrogen bond constraint to mainchain NH of hinge
residue M793 was required, as experimentally observed in the
case of quinoline/quinolizine scaffolds. The grid box was centered
using coordinate center of the core structure of corresponding x-
ray ligand as template. Graphical illustrations were generated
using, Maestro, and PyMOL software of Schrödinger.
N-(3-Ethynylphenyl)-6,7-dimethoxyquinazolin-4-amine
(4)
colourless solid (74 %, 251 mg, 0.824 mmol) MP 237-239 oC; 1H
NMR (500 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.85 (s, 1H), 8.38 (s,
1H), 7.88 (t, J = 1.8 Hz, 1H), 7.79 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H),
7.49 (t, J = 7.8 Hz, 1H), 7.40 (dt, J = 7.7, 1.3 Hz, 1H), 7.37 (s, 1H),
4.28 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H). 13C NMR (125 MHz,
DMSO-d6) δ 158.1, 156.3, 150.2, 148.8, 137.4, 136.0, 129.2,
129.2, 127.6, 125.3, 122.0, 107.4, 104.1, 99.9, 82.9, 81.3, 57.0,
56.5. HRMS m/z [M+H]+ calcd for C18H16N3O2: 306.1243, found
306.1230, LC tR = 3.41 min, >98% Purity.
N-(3-Ethynylphenyl)-6-methoxyquinazolin-4-amine (5) yellow
solid (56%, 119 mg, 0.432 mmol) MP 176-178 oC; 1H NMR (400
MHz, DMSO-d6) δ 11.91 (s, 1H), 8.89 (s, 1H), 8.56 (d, J = 2.7 Hz,
1H), 7.96 (d, J = 9.1 Hz, 1H), 7.92 (t, J = 1.8 Hz, 1H), 7.83 (ddd,
J = 8.1, 2.2, 1.2 Hz, 1H), 7.73 (dd, J = 9.1, 2.6 Hz, 1H), 7.54 –
7.47 (m, 1H), 7.42 (dt, J = 7.7, 1.3 Hz, 1H), 4.29 (s, 1H), 4.02 (s,
3H). 13C NMR (101 MHz, DMSO-d6) δ 159.2, 159.0, 148.8, 137.1,
133.5, 129.6, 129.1, 127.8, 127.1, 125.5, 122.0, 121.4, 114.8,
104.8, 82.9, 81.4, 56.9. HRMS m/z [M+H]+ calcd for C17H14N3O:
276.1137 found = 276.1127; LC tR = 3.47 min, >98% Purity.
Hydration Site Analysis
Hydration site analysis calculated with WaterMap
(Schrödinger Release 2018-4: WaterMap, Schrödinger, LLC,
New York, NY, 2018.). The structure of EGFR (PDB:3W2S) was
prepared with Protein Preparation Wizard (as above).5 Waters
N-(3-Ethynylphenyl)-7-methoxyquinazolin-4-amine
(6)
colourless solid (68 %, 241 mg, 0.874 mmol) MP 223-225 oC; 1H
5
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10.1002/cmdc.201900428
ChemMedChem
COMMUNICATION
NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.96 (d, J = 9.3 Hz,
1H), 8.91 (s, 1H), 7.89 (t, J = 1.9 Hz, 1H), 7.78 (ddd, J = 8.1, 2.2,
1.2 Hz, 1H), 7.59 – 7.36 (m, 4H), 4.29 (s, 1H), 3.98 (s, 3H). 13C
NMR (101 MHz, DMSO-d6) δ 164.9, 159.2, 150.9, 141.0, 137.1,
129.5, 129.2, 127.7, 127.2, 125.4, 122.0, 119.0, 107.3, 100.2,
82.9, 81.4, 56.3. HRMS m/z [M+H]+ calcd for C17H14N3O:
276.1137, found 276.1127, LC tR = 3.34 min, >98% Purity.
1H), 7.34 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 2.7 Hz, 1H), 7.16 (dd, J
= 9.2, 2.7 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.87 – 6.67 (m, 2H),
3.90 (s, 3H), 2.39 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.1,
159.9, 150.9, 150.8, 150.2, 147.7, 141.6, 138.2, 131.5, 129.0 (s,
2C), 127.5 (s, 2C), 124.9, 123.5, 121.8, 116.5, 114.3, 113.1, 109.9,
107.8, 100.6, 55.3, 21.0. HRMS m/z [M+H]+ calcd for C24H22N3O3:
400.1661 found = 400.1647; LC tR = 4.21 min, >98% Purity.
4-((3-Ethynylphenyl)amino)-6,7-dimethoxyquinoline-3-
N-(4-((6,7-Dimethoxyquinolin-4-yl)amino)phenyl)-4-
carbonitrile (7) beige solid (69 %, 229 mg, 0.694 mmol) MP 241-
methylbenzamide
mustard
solid
(16)
4-chloro-6,7-
o
1
243 C; H NMR (400 MHz, DMSO-d6) δ 11.46 – 11.29 (s, 1H),
8.98 (s, 1H), 8.25 (s, 1H), 7.73 – 7.29 (m, 5H), 4.30 (s, 1H), 4.00
(s, 3H), 3.99 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 155.4,
152.6, 150.2, 147.2, 138.0, 130.9, 129.6, 129.0, 126.7, 122.6,
114.2, 113.0, 103.8, 101.4, 86.5, 82.7, 81.8, 56.9, 56.4. HRMS
m/z [M+H]+ calcd for C20H16N3O2: 330.1243 found = 330.1237; LC
tR = 4.70 min, >98% Purity.
dimethoxyquinoline (200 mg, 0.89 mmol) and N-(4-aminophenyl)-
4-methylbenzamide (222.6 mg, 0.98 mmol) Pd2(dba)3 (122.8 mg,
0.13 mmol), XPhos (64 mg, 0.13 mmol) and caesium carbonate
(874 mg, 2.68 mmol) were all suspended in DMF 15 mL and
o
degassed for 5 min. The mixture was held at reflux at 140 C for
18 h. The crude mixture was then passed through a plug of celite
545 before been purified by flash chromatography 20- 100%
EtOAc:hexane followed by 1–5 % methanol/ethyl acetate and
solvent removed under reduced pressure to yield the product as
a free following solid: (72 %, 266 mg, 0.64 mmol) MP 122-125 oC
1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.68 (s, 1H), 8.26
(d, J = 5.3 Hz, 1H), 8.09 – 7.72 (m, 4H), 7.69 (s, 1H), 7.63 – 7.26
(m, 4H), 7.24 (s, 1H), 6.73 (d, J = 5.3 Hz, 1H), 3.92 (d, J = 13.4
Hz, 6H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.6,
152.0, 148.6, 148.5, 147.4, 146.1, 141.9, 136.6, 135.7, 132.6,
129.4 (s, 2C), 128.1 (s, 2C), 123.6 (s, 2C), 121.8 (s, 2C), 114.1,
108.6, 101.4, 100.7, 56.4, 55.9, 21.5. HRMS m/z [M+H]+ calcd for
C25H24N3O3: 414.1818 found = 414.1808; LC tR = 5.05 min, >98%
Purity.
4-[(3-Ethynylphenyl)amino]-6-methoxyquinoline-3-
carbonitrile (8) yellow solid (58 % 199 mg, 0.663 mmol) MP 245-
o
1
247 C; H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 9.02 (s,
1H), 8.40 (d, J = 2.6 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.72 (dd, J
= 9.2, 2.6 Hz, 1H), 7.61 (m, 1H), 7.57 - 7.40 (m, 3H), 4.31 (s, 1H),
4.00 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 158.9, 153.7,
147.3, 137.7, 133.8, 131.3, 129.6, 129.3, 127.0, 126.2, 123.3,
122.6, 120.0, 114.1, 104.3, 86.6, 82.7, 81.8, 56.8. HRMS m/z
[M+H]+ calcd for C19H14N3O: 300.1137 found = 300.1135; LC tR =
4.90 min, >98% Purity.
4-[(3-Ethynylphenyl)amino]-7-methoxyquinoline-3-
carbonitrile (9) yellow solid (62 %, 212 mg, 0.708 mmol) MP 245-
4-(tert-Butyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)amino)-2-
hydroxyphenyl)benzamide (17) as a bright yellow solid (68 %,
103 mg, 0.218 mmol) MP decomposed >260 C; H NMR (400
o
1
247 C, H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.06 (s,
1H), 8.88 (d, J = 9.4 Hz, 1H), 7.75 – 7.28 (m, 6H), 4.31 (s, 1H),
o
1
3.98 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.0, 154.1, 149.8, MHz, DMSO-d6) δ 10.62 (s, 1H), 10.49 (s, 1H), 9.53 (s, 1H), 8.34
141.0, 137.6, 131.3, 129.6, 129.3, 127.1, 126.7, 122.6, 119.0,
114.0, 112.6, 101.7, 86.2, 82.7, 81.8, 56.3. HRMS m/z [M+H]+
calcd for C19H13N3O: 300.1137 found = 300.1130; LC tR = 4.40
min, >98% Purity.
(d, J = 7.0 Hz, 1H), 8.14 (s, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.56 (d,
J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H),
6.76 (d, J = 6.8 Hz, 1H), 3.99 (d, J = 14.2 Hz, 6H), 1.32 (s, 9H).
13C NMR (101 MHz, DMSO-d6) δ 165.1, 154.7, 154.5, 153.2,
150.0, 149.4, 139.7, 135.3, 134.2, 131.5, 127.4 (s, 2C), 125.3 (s,
2C), 125.1, 124.3, 115.8, 112.8, 111.5, 102.7, 99.9, 99.2, 56.7,
56.1, 34.7, 30.9 (s, 3C). HRMS m/z [M+H]+ calcd for C28H30N3O4:
472.2236 found = 472.2218; LC tR = 5.15 min, >98% Purity.
N-{4-[(6,7-Dimethoxyquinolin-4-yl)amino]-2-hydroxyphenyl}-
4-methylbenzamide (13) as a colorless solid (85 %, 151 mg,
0.351 mmol) MP decomposed >280 oC; 1H NMR (400 MHz,
DMSO-d6) δ 10.58 (s, 1H), 10.46 (s, 1H), 9.53 (s, 1H), 8.35 (d, J
= 6.9 Hz, 1H), 8.12 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.44 (s, 1H),
7.35 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.5,
2.4 Hz, 1H), 6.77 (d, J = 6.9 Hz, 1H), 3.99 (d, J = 11.8 Hz, 6H),
6,7-Dimethoxy-N-(4-((4-methylbenzyl)oxy)phenyl)quinolin-4-
amine (18) as a light yellow/cyan solid (74 %, 126 mg, 0.315
mmol) MP 158-160 oC; 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s,
2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 165.1, 154.6, 153.2, 1H), 8.29 (d, J = 7.0 Hz, 1H), 8.15 (s, 1H), 7.45 (s, 1H), 7.37 (dd,
150.1, 149.4, 141.8, 139.8, 135.3, 134.3, 131.4, 129.1 (s, 2C),
J = 8.5, 2.5 Hz, 4H), 7.29 – 7.04 (m, 4H), 6.55 (d, J = 6.9 Hz, 1H),
127.6 (s, 2C), 125.1, 124.5, 115.8, 112.8, 111.5, 102.6, 99.9, 99.2, 5.11 (s, 2H), 3.99 (s, 3H), 3.96 (s, 3H), 2.32 (s, 3H). 13C NMR (101
56.7, 56.2, 21.0. HRMS m/z [M+H]+ calcd for C25H24N3O4:
430.1767 found = 430.1751; LC tR = 4.46 min, >98% Purity.
MHz, DMSO-d6) δ 157.3, 154.5, 153.6, 149.3, 139.8, 137.2,
135.3, 133.8, 130.1, 129.0 (s, 2C), 127.9 (s, 2C), 127.2 (s, 2C),
115.9 (s, 2C), 111.3, 102.7, 99.9, 98.8, 69.5, 56.7, 56.1, 20.8.
HRMS m/z [M+H]+ calcd for C25H25N2O3: 401.1865 found =
401.1849; LC tR = 5.16 min, >98% Purity.
N-(2-Hydroxy-4-((6-methoxyquinolin-4-yl)amino)phenyl)-4-
methylbenzamide (14) as a yellow solid (56 %, 89 mg, 0.232
mmol) MP decomposed >280 oC; 1H NMR (500 MHz, DMSO-d6)
δ 10.73 (s, 1H), 10.49 (s, 1H), 9.54 (s, 1H), 8.43 (d, J = 6.8 Hz,
1H), 8.19 (d, J = 2.6 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.92 (dd, J
= 8.4, 6.8 Hz, 3H), 7.66 (dd, J = 9.3, 2.6 Hz, 1H), 7.35 (d, J = 8.0
Hz, 2H), 7.09 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.5, 2.4 Hz, 1H),
6.84 (d, J = 6.8 Hz, 1H), 3.99 (s, 3H), 2.40 (s, 3H). 13C NMR (126
MHz, DMSO-d6) δ 165.1, 158.0, 153.8, 150.2, 141.8, 140.7, 134.1,
133.6, 131.4, 129.1 (s, 2C), 127.6 (s, 2C), 125.3, 125.2, 124.6,
122.1, 118.4, 115.8, 112.8, 102.8, 99.6, 56.5, 21.0. HRMS m/z
[M+Na]+ calcd for C24H21N3O3Na: 422.1481 found = 422.1185; LC
tR = 4.23 min, >98% Purity.
N-(4-((6,7-Dimethoxyquinolin-4-yl)amino)phenyl)acetamide
(19) as a grey solid (77 %, 144 mg, 0.427 mmol) MP decomposed
>260 oC HRMS m/z [M+H]+ calcd for C19H20N3O3: 338.1505 found
= 338.1489; LC tR = 3.09 min, >98% Purity. Consistent with
previous report.26
Cell Culture Biology Method
Chordoma cell lines UCH-1 and UCH-2 were cultured in 4:1
IMDM:RPMI supplemented with 10 % Fetal Bovine Serum 1 %
Penicillin/Streptomycin in gel-coated flasks. WS1 and A-431 cells
were cultured in DMEM supplemented with 10 % Fetal Bovine
Serum 1 % Penicillin/Streptomycin. UCH-1 and UCH-2 were
seeded at 250 cells/well in gel-coated 384 well plates. WS1 cells
were seeded at 400 cells/well in 384 well plates, and A-431 cells
were seeded at 500 cells/well in 384 well plates. Cells were
N-(2-Hydroxy-4-((7-methoxyquinolin-4-yl)amino)phenyl)-4-
methylbenzamide (15) as a yellow solid (67 %, 111 mg, 0.278
mmol) MP decomposed >270 oC; 1H NMR (500 MHz, DMSO-d6)
δ 9.92 (s, 1H), 9.46 (s, 1H), 8.83 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H),
8.28 (d, J = 9.3 Hz, 1H), 8.06 – 7.79 (m, 2H), 7.66 (d, J = 8.5 Hz,
6
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10.1002/cmdc.201900428
ChemMedChem
COMMUNICATION
[12] Magnaghi, P.; Salom, B.; Cozzi, L.; Amboldi, N.; Ballinari, D.;
Tamborini, E.; Gasparri, F.; Montagnoli, A.; Raddrizzani, L.;
Somaschini, A.; Bosotti, R.; Orrenius, C.; Bozzi, F.; Pilotti, S.;
Galvani, A.; Sommer, J.; Stacchiotti, S.; Isacchi, A. Mol Cancer
Ther. 2018, 17, 603-613.
[13] Asquith, C. R. M.; Naegeli, K. M.; East, M. P.; Laitinen, T.;
Havener, T. M.; Wells, C. I.; Johnson, G. L.; Drewry, D. H.;
Zuercher, W. J.; Morris, D. C. J Med Chem. 2019, 62, 4772-
4778.
treated with compound at 24 h after plating, and cell viability was
assessed at 72 h using alamarBlue (ThermoFisher, USA).
Fluorescence was measured using Tecan Infinite 200 PRO plate
reader with excitation at 535 nM and emission at 590 nM. IC50
values were determined by nonlinear regression using Graphpad
PrismTM software.
Acknowledgements
[14] Knight, Z. A.; Shokat, K. M. Chem Biol. 2005, 12, 621-637.
[15] Asquith, C. R. M.; Laitinen, T.; Bennett, J. M.; Godoi, P. H.;
East, M. P.; Tizzard, G. J.; Graves, L. M.; Johnson, G. L.;
Dornsife, R. E.; Wells, C. I.; Elkins, J. M.; Willson, T. M.;
Zuercher, W. J. ChemMedChem 2018, 13, 48-66.
[16] Asquith, C. R. M.; Berger, B. T.; Wan, J.; Bennett, J. M.;
Capuzzi, S. J.; Crona, D. J.; Drewry, D. H.; East, M. P.; Elkins,
J. M.; Fedorov, O.; Godoi, P. H.; Hunter, D. M.; Knapp, S.;
Mꢀller, S.; Torrice, C. D.; Wells, C. I.; Earp, H. S.; Willson, T.
M.; Zuercher, W. J. J. Med. Chem. 2019, 62, 2830-2836.
[17] Fabian, M. A.; Biggs, W. H., 3rd; Treiber, D. K.; Atteridge, C.
E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.;
Edeen, P. T.; Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.;
Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai,
A. G.; Lelias, J. M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A.
M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.; Lockhart, D.
J. Nat Biotechnol 2005, 23, 329-336.
The SGC is a registered charity (number 1097737) that receives
funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim,
Canada Foundation for Innovation, Eshelman Institute for
Innovation, Genome Canada, Innovative Medi-cines Initiative
(EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck
KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario
Ministry of Economic Development and Innovation, Pfizer, São
Paulo Research Foundation-FAPESP, Takeda, and Wellcome
[106169/ZZ14/Z]. We also thank CSC - IT Center for Science Ltd.
Finland for the use of their facilities, software licenses and
computational resources. We are grateful Dr. Brandie Ehrmann
for LC-MS/HRMS support provided by the Mass Spectrometry
Core Laboratory at the University of North Carolina at Chapel Hill.
We also thank the EPSRC UK National Crystallography Service
for funding and collection of the crystallographic data for 13. We
would also like to thank Prof. Anthony J. Hickey and David C.
Morris (UNC Catalyst for Rare Diseases) and Karl M. Koshlap
(UNC Eshelman School of Pharmacy) for useful discussions.
[18] Cappel, D.; Sherman, W.; Beuming, T. Curr Top Med Chem.
2017, 17, 2586-2598.
[19] Robinson, D. D.; Sherman, W.; Farid, R. ChemMedChem.
2010, 5, 618-627.
[20] Schrödinger suite 2015-3: Maestro, version 10.3; Ligprep,
version 2.8; QM-Polarized Ligand Docking; Glide version 6.8,
Jaguar version 8.9, QSite version 6.8, Schrödinger, LLC, New
York, NY, 2015)
[21] Asquith C. R. M., Treiber D. K., Zuercher W. J. Bioorg. Med.
Chem. Lett. 2019, 29, 1727-1731.
Keywords: Epidermal growth factor receptor (EGFR) • 4-
anilinoquinoline • 4-anilinoquinazoline • Non-small cell lung
cancer (NSCLC) • EGFR Asp855 (D855) • Chordoma
References
[22] Compound 13 - CCDC number 1894101
[23] Sogabe, S.; Kawakita, Y.; Igaki, S.; Iwata, H.; Miki, H.; Cary, D.
R.; Takagi, T.; Takagi, S.; Ohta, Y.; Ishikawa, T. ACS Med
Chem Lett. 2012, 4, 201-205.
[1]
[2]
Cancer Fact sheet N°297 WHO, 2018.
(a) Ferguson, F. M.; Gray, N. S. Nat Rev Drug Discov. 2018,
17, 353-377; (b) http://www.brimr.org/PKI/PKIs.htm
Lynch, T. J.; Bell, D. W.; Sordella, R.; Gurubhagavatula, S.;
Okimoto, R. A.; Brannigan, B. W.; Harris, P. L.; Haserlat, S.
M.; Supko, J. G.; Haluska, F. G.; Louis, D. N.; Christiani, D. C.;
Settleman, J.; Haber, D. A. N. Engl. J. Med. 2004, 350, 2129-
2139.
Maemondo, M.; Inoue, A.; Kobayashi, K.; Sugawara, S.;
Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.;
Kinoshita, I.; Fujita, Y.; Okinaga, S.; Hirano, H.; Yoshimori, K.;
Harada, T.; Ogura, T.; Ando, M.; Miyazawa, H.; Tanaka, T.;
Saijo, Y.; Hagiwara, K.; Morita, S.; Nukiwa, T. N. Engl. J. Med.
2010, 362, 2380-2388.
[24] Dixit, A.; Verkhivker, G. M. Comput Math Methods Med. 2014,
2014, 653487.
[3]
[25] Harder, E.; Damm, W.; Maple, J.; Wu, C.; Reboul, M.; Xiang, J.
Y.; Wang, L.; Lupyan, D.; Dahlgren, M. K.; Knight, J. L.; Kaus,
J. W.; Cerutti, D. S.; Krilov, G.; Jorgensen, W. L.; Abel, R.;
Friesner, R. A. J Chem Theory Comput. 2016, 12, 281-296.
[26] Kubo, K.; Shimizu, T.; Ohyama, S.; Murooka, H.; Iwai, A.;
Nakamura, K.; Hasegawa, K.; Kobayashi, Y.; Takahashi, N.;
Takahashi, K.; Kato, S.; Izawa, T.; Isoe, T. J Med Chem. 2005,
48, 1359-1366.
[4]
[5]
Wood, E. R.; Truesdale, A. T.; McDonald, O. B.; Yuan, D.;
Hassell, A.; Dickerson, S. H.; Ellis, B.; Pennisi, C.; Horne, E.;
Lackey, K.; Alligood, K. J.; Rusnak, D. W.; Gilmer, T. M.;
Shewchuk, L. Cancer Res. 2004, 64, 6652-6659.
Sigismund, S.; Avanzato, D.; Lanzetti, L. Mol Oncol. 2018, 12,
3-20.
George, B.; Bresson, D.; Herman, P.; Froelich, S. Neurosurg
Clin N Am. 2015, 26, 437-452.
Ferraresi, V.; Nuzzo, C.; Zoccali, C.; Marandino, F.; Vidiri, A.;
Salducca, N.; Zeuli, M.; Giannarelli, D.; Cognetti, F.; Biagini, R.
BMC Cancer. 2010, 28, 22.
[6]
[7]
[8]
[9]
Akhavan-Sigari, R.; Gaab, M.; Rohde, V.; Abili, M.; Ostertag,
H. Anticancer Res. 2014, 34, 623-630.
[10] Magnaghi, P.; Salom. B.; Cozzi, L.; Amboldi, N.; Ballinari, D.;
Tamborini, E.; Gasparri, F.; Montagnoli, A.; Raddrizzani, L.;
Somaschini, A.; Bosotti, R.; Orrenius, C.; Bozzi, F.; Pilotti, S.;
Galvani, A.; Sommer, J.; Stacchiotti, S.; Isacchi, A. Mol Cancer
Ther. 2018, 17, 603-613.
[11] Scheipl, S.; Barnard, M.; Cottone, L.; Jorgensen, M.; Drewry,
D. H.; Zuercher, W. J.; Turlais, F.; Ye, H.; Leite, A. P.; Smith,
J. A.; Leithner, A.; Möller, P.; Brüderlein, S.; Guppy, N.; Amary,
F.; Tirabosco, R.; Strauss, S. J.; Pillay, N.; Flanagan, A. M. J
Pathol. 2016, 239, 320-334.
7
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ChemMedChem
COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here.
Preparation of a series of structurally focused modular arrays of quin(az)oline-based inhibitors of the epidermal growth factor receptor
(EGFR) were investigated against non-small cell lung cancer and chordomas with the identification of potent relatively non-toxic
compounds. Several key structural features including an interaction with the EGFR ATP binding site were probed, along with the
specific targeting of the active site water network.
8
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