Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type FAK-targeted inhibitors as potential tumour imaging agents

Article abstract of DOI:10.1016/j.bmcl.2020.127452

As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly expressed in most types of tumours and is thus regarded as a promising antitumour target. In this study, a series of novel 2,4-diaminopyrimidine FAK-targeted

Full text of DOI:10.1016/j.bmcl.2020.127452

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Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyr‐
imidine-type FAK-targeted inhibitors as potential tumour imaging agents
Yueheng Qi, Ye Li, Yu Fang, Bingchao Qiang, Hang Gao, Shuxia Wang,
Huabei Zhang
PII:
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https://doi.org/10.1016/j.bmcl.2020.127452
BMCL 127452
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24 July 2020
Please cite this article as: Qi, Y., Li, Y., Fang, Y., Qiang, B., Gao, H., Wang, S., Zhang, H., Design, synthesis,
and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type FAK-targeted inhibitors as potential
tumour imaging agents, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.
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Design, synthesis, and biological evaluation of F-18-labelled 2, 4-diaminopyrimidine-type
FAK-targeted inhibitors as potential tumour imaging agents
Yueheng Qia, Ye Lia, Yu Fangb, Bingchao Qianga, Hang Gaoa, Shuxia Wanga, and Huabei
Zhanga,*
aKey Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry,
Beijing Normal University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, China
bCollege of Chemistry and Chemical Engineering, Anyang Normal University, No. 436 Xian'ge
Road, Anyang 455000, Henan Province, China
Corresponding author
H. Zhang
Tel./fax: +86-10-58802012
E-mail: hbzhang@bnu.edu.cn
1

Abstract
As a type of intracellular nonreceptor tyrosine kinase, focal adhesion kinase (FAK) can be highly
expressed in most types of tumours and is thus regarded as a promising antitumour target. In this
study, a series of novel 2,4-diaminopyrimidine FAK-targeted inhibitors were designed,
synthesized and characterized by 1H NMR, 13C HNMR, and HRMS spectra. These compounds,
with an IC50 range of 5.0-205.1 nM, showed superior inhibitory activity against FAK. Two
compounds, [18F]Q-2 and [18F]Q-4, with respective IC50 values of 5.0 nM and 21.6 nM, were
labelled by 18F, accompanied by evaluation of their biodistributions. For [18F]Q-2, at 30 min
post-injection, promising target-to-nontarget ratios were observed, associated with tumour/blood,
tumour/muscle, and tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. The results indicated
that [18F]Q-2 is a potential PET tracer for tumour diagnosis.
Keywords: FAK inhibitor, F-18 labelled, Tumour imaging agents
2

Focal adhesion kinase (FAK), located in the focal adhesion, is a type of nonreceptor
tyrosine kinase. It was identified as the substrate of the Src oncogene by Schaller et al.1
When extracellular signals are transmitted to FAK by integrins, cytokine receptors,
growth factor receptors, and G protein coupled receptors, FAK is activated and triggers various
downstream signals, controlling cell survival, growth, angiogenesis, migration, and invasion.2
Numerous studies have demonstrated high expression of FAK in various cancers,
including ovarian cancer,3 lung cancer,4 pancreatic cancer,5 colorectal cancer,6 breast cancer,7
and oesophageal cancer.8
The increase in the expression and activity of FAK is an important indicator of cancer
prognosis. Thus, FAK can be used as a potential prognostic marker and anticancer drug
candidate.9,10
Most ATP-competitive FAK inhibitors are derivatives of 2,4-diaminopyrimidine (Fig. 1).
TAE226 can inhibit the activity of FAK by blocking the FAK-ATP binding sites and the
phosphorylation sites (Y397 and Y861) of FAK.11 PF-562271, also known as VS-6062, shows
antitumour effects by inhibiting the interaction of FAK, PyK2 and ATP.12 Defactinib, also
known as VS-6063, is a kind of ATP-competitive FAK inhibitor. This compound demonstrates
better dose-dependent performances than PF-562271, and it has entered a phase II clinical trial to
assess the clinical effects of VS-6063 in patients suffering from advanced ovarian cancer,
malignant pleural mesothelioma and non-small cell lung cancer.13
3

F
Cl
F
O
F
F
N
F
F
S
N
O
N
O
N
NH
O
HN
N
O
S
N
NH
N
HN
O
HN
N
N
H
N
O
N
H
N
N
N
O
HN
O
TAE226
PF-562271
N
VS-6063
H
Fig. 1. Classic FAK inhibitors that have been reported.
Based on the high expression of FAK in various types of cancers, a series of
2,4-diaminopyrimidine-type FAK-targeted inhibitors were synthesized in this study. In addition,
the compounds were radioactively labelled to develop potential PET imaging agents for tumour
diagnosis.
The general synthesis method is illustrated in Fig. 2. The activities of the three active
sites on ring A in decreasing order were 4, 2, and 5. First, nucleophilic substitution took place
only between the Cl atom in the 4-position of ring A and the amino group on ring B in an
alkaline environment, and then, nucleophilic substitution occurred between the amino group on
ring C and the Cl atom in the 2-position of ring A in a high-temperature acidic environment. The
groups in the 5-position of ring A were relatively stable under the first two conditions, without
participating in the reactions. Rings A and C were modified to obtain reference standards with
better IC50 values and precursors suitable for radioactive labelling.
4

R1
Cl
5
N
A
N
2
4
Cl
NH2
C
NH2
B
O
S
N
N
O
O
O
O
R2
Fig. 2. Linkage of rings A, B and C.
As shown in Scheme 1, the amino intermediate 3 of ring B was obtained by nitro
reduction after nucleophilic substitution by 1, and 5a-e was acquired by the connection of 3 to
the 4-position of ring A in the K2CO3 alkaline environment.
R1
Cl
R1
N
N
NO2
N
NH2
N
NO2
N
O
S
O
S
Cl
N
a
Cl
N
NH
N
N
Cl
b
O
S
N
O
O
c
N
O
1
2
3
4a-e
5a-e
Cl
O
Br
F
CH3
R1=
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
Scheme 1a
aConditions: (a) NaH, DMF, 0 °C to rt; (b) H2, 10% Pd/C, MeOH, rt; (c) K2CO3, DMF, 90 °C.
One of the three methoxy groups on ring C was selectively demethylated to a hydroxyl
group, leading to an active site, which was modified into other structures, and then, a series of
aniline compounds (Scheme 2) were obtained by the reduction of the nitro group.
5

NH2
OH
NO2
COOH
NO2
a
b
c
O
O
O
O
O
O
O
O
O
O
OH
6
7
8
9
c
d
NH2
NH2
NO2
c
O
O
O
O
O
O
O
O
O
R2
R2
10
11a, 11b
12a, 11b
R2=
F
OH
11a 11b
12a 12b
Scheme 2a
aConditions: (a) HNO3, AcOH, 40 °C; (b) BCl3 (1.0 mol/L in DCM), DCM, 40 °C; (c) H2, 10%
Pd/C, MeOH, rt.
Scheme 3 shows that rings C and A were successfully connected with the catalysis of
p-toluene sulfonic acid in DMF at 110 ℃, and finally, a series of labelled precursors and
standards were obtained.
R1
N
R1
NH2
N
HN
O
N
O
NH
O
S
a
N
Cl
N
NH
O
S
N
O
O
N
O
O
O
R3
N
O
R3
6

9,10,12a,12b
5a-e
13-14 Q-1-Q-5
Cl
O
Br
F
CH3
R3=
H
R1=
H3C
5a
5b
5c
5d
5e
OH
F
9
10
12a
12b
Br
CH3
Br
Cl
R1=
R3=
F
CH3
O
H
H
F
F
F
F
F
13
Scheme 3a
aConditions: (a) TsOH, DMF, 110 °C.
14
Q-1
[19F]Q-2 Q-3 [ 19F]Q-4
Q-5
The FAK-IC50 values of 5 standards are shown in Table 1, with PF-562271 as the control.
Among these 19F standards, the compounds with the best kinase activity ([19F]Q-2 and [19F]Q-4)
were screened for 18F radiolabeling to obtain their corresponding 18F radioactive products
([18F]Q-2 and [18F]Q-4), and studied their biodistribution. Therefore, we mainly tested the
FAK-IC50 values of 5 standards. The substituent groups in the 5-position of pyrimidine rings of
these 5 standards were Cl, Br, F, methyl and methoxyl groups. The activity increased by
substitution of Cl by Br, with an IC50 value of 5.0 nM. However, the activity decreased after
substitution of Cl by F. A space may be present in the deepest active pocket of FAK. A better
hydrophobic effect was observed between the FAK protein and five substituent groups on the
pyrimidine ring when they were replaced by larger ones. However, the volume of the substituent
groups could not be excessively large. For example, the activity obviously decreased after the
substitution of Cl by a methoxyl group.
7

R1
N
HN
N
O
NH
O
S
N
N
O
O
O
F
Compd
R1
IC50 (nM)
ClogP
1.20
Cl
Q-1
22.2
5.0
Br
F
[19F]Q-2
Q-3
0.99
1.03
0.76
80.7
21.6
CH3
O
[19F]Q-4
Q-5
0.2
205.1
6.9
Pf-562271
-0.71
Table 1. The inhibition of the enzyme activity of the compounds against FAK in vitro.
Fig. 3 displays the docking model with [19F]Q-2 and Q-5 as the examples. Two hydrogen
bonds were formed between the N atom of the pyridine ring and aniline NH and the residue
Cys502. Hydrogen bonds could also be formed between the terminal F atom and Arg426.
Moreover, hydrophobic interactions occurred among ring A, Ala452 and Leu553, enhancing the
selectivity. The FAK inhibitors in this article were all designed using the above design concepts.
Through docking diagram B, it can be found that there is indeed a space in the deepest pocket of
the FAK protein. Therefore, appropriately increasing the volume of substituent R1 on the
pyrimidine ring is conducive to the combination of the inhibitor and the protein. Compound Q-5
had a relatively longer R1 substituent than the other compounds, the N atom of the pyrimidine
ring could not form the more stable hydrogen bond with the Cys502 residue, so that the activity
8

was significantly reduced. The docking diagrams of the other 19F standards were in the
Supporting Information.
9

Fig. 3. The docking model of the [19F]Q-2, Q-5 and FAK active pocket. PDB code: 3BZ3.
The docking diagrams of Q-1, [19F]Q-2, Q-3 and [19F]Q-4 were similar, to study the
structure-activity relationship more accurately, we conducted a molecular dynamics simulation
study on five 19F standards. In this study, MD modelling was successfully implemented on five
types of FAK inhibitor complexes that were at scales of 35 ns. Specifically, equilibrium was
reached in Complexes Q-1, Q-3 and Q-5 in 3 ns, while that in Complexes [19F]Q-2 and [19F]Q-4
was reached in 7 ns and 10 ns, respectively. According to Fig. 4, the RMSD values of
Complexes Q-1, [19F]Q-2, Q-3, [19F]Q-4 and Q-5 were 1.3 nm, 2.5 nm, 1.5 nm, 3.25 nm, and
2.0 nm, respectively, with a deviation of less than 3.25 nm. Among them, Complex Q-1 had the
most reliable stability. Since the MD modelling trajectories of all five complexes were stable in
10 ns, it was reasonable to use the snapshots taken from 10 ns to 35 ns for calculation and
decomposition of the binding free energy.
Fig. 4. The root-mean-square deviations (RMSD) of the backbone atoms relative to their initial
10

minimized complex structures as a function of time.
As shown in Table 2, both van der Waals forces and electrostatic interactions between
molecules were important contributors to the binding, while the polar solvation (ΔGsolele) was not
conducive to the binding. The ΔGsolele data of compounds Q-1, Q-3 and [19F]Q-4 were more
unfavorable for binding than Q-2, and the FAK-IC50 value obtained in the experiments was in
good agreement with our testing binding free energy results (ΔG bind) in terms of their rankings.
Docking and molecular dynamics complemented each other, which also explained the
structure-activity relationship well.
Contribution
Q-1
[19F]Q-2
Q-3
[19F]Q-4
Q-5
ΔEintele
ΔEintvdw
ΔGsolnopol
ΔGsolele
-4.4654
-56.5026
-6.5157
25.8695
-63.0183
21.4041
13.4337
-28.1806
22.2
-5.2575
-54.0008
-6.6487
25.5209
-60.6495
20.2634
11.2945
-29.0915
5.0
-14.3267
-53.6563
-6.6064
35.2083
-60.2627
20.8816
12.7586
-26.6225
80.7
-7.6561
-52.7025
-6.2252
27.7072
-58.9277
20.0511
11.9642
-26.9124
21.6
-15.8678
-57.2629
-7.1495
38.9902
-64.4124
23.1224
15.3801
-25.9099
205.1
a
ΔGsol
b
ΔGele
−TΔS
ΔG bind
IC50 (nM)
aThe polar/nonpolar ( ΔGintvdw+ΔGsolnopol) contributions;
bThe electrostatic ( ΔEintele+ΔGsolele) contributions;
11

All energies were averaged over 500 snapshots and were given in kcal/mol;
Table 2. Results of eight energy calculations by MM/GBSA of amber 14.
As shown in Scheme 4, two compounds with optimum IC50 values were chosen to be
labelled with 18F using a two-step labelling method. First, [18F]-fluoroethyl-tosylate ([18F]16)
was obtained by Method a, and it was then purified by HPLC. Radioactive products of [18F]Q-2
and [18F]Q-4 were obtained by the reaction of purified [18F]-fluoroethyl-tosylate ([18F]16) with
precursors 13 and 14.
K18
a
F
18F
TsO
OTs
OTs
15
[18F]16
Br
N
Br
N
HN
N
O
NH
18F
O
S
HN
N
NH
OTs
N
O
N
S
N
O
b
O
N
O
O
O
O
OH
18F
13
[18F]Q-2
N
N
18F
HN
N
O
NH
O
HN
N
O
NH
OTs
N
O
S
N
S
N
O
b
O
N
O
O
O
OH
18F
14
[18F]Q-4
Scheme 4a
aConditions: (a) [18F]KF, Kryptofix-2.2.2., K2CO3, MeCN, 110 °C; (b) K2CO3, MeCN, 120 °C.
12

Fig. 5 shows the HPLC chromatograms after coinjection of the HPLC purified [18F]Q-2
and [18F]Q-4 (radiochemical purity > 98%) and the corresponding standards [19F]Q-2 and
[19F]Q-4. The retention times of [18F]Q-2 and [18F]Q-4 were 16.6 min and 14.3 min,
respectively, which matched with those of the corresponding 19F standards [19F]Q-2 (16.4 min)
and [19F]Q-4 (14.2 min) within admissible error, respectively. Estimated by comparing the UV
peak intensity of purified 18F-labelled compounds with reference nonradioactive compounds, the
molar activity ranged from 45 to 52 GBq/μmol at the end of synthesis.
Fig. 5. The coinjection analysis (left) of [18F]Q-2 and [19F]Q-2 on a semipreparation column
with the eluent of MeOH/H2O=7/3 and a flow rate of 4 mL/min; the coinjection analysis (right)
of [18F]Q-4 and [19F]Q-4 on a semipreparation column with the eluent of MeOH/H2O=6.7/3.3
and a flow rate of 4 mL/min. The HPLC profile data were exported from the *.lcd files by
Shimadzu LCSolution Software and were graphically interpreted and coordinate translated by
Origin 8.0.
Table 3 shows the biodistribution data of the [18F]Q-2 compound in S180-bearing mice,
and the corresponding column diagram is shown in Fig. 6. The results indicated that the uptake
of [18F]Q-2 in tumours at 15 min postinjection was the largest, which was 3.68±0.18% ID/g.
Tumour/blood, tumour/muscle, and tumour/bone were 1.17, 2.99 and 2.19, respectively. The
13

uptake of [18F]Q-2 in the liver at 15 min postinjection was high, but it decreased obviously at 30
min and was 5.73±0.77% ID/g. At this time, the uptake of [18F]Q-2 in the tumour was
2.85±0.10%ID/g, which was only lower than those of the liver and kidney, with tumour/blood,
tumour/muscle, and tumour/bone ratios of 0.91, 1.60 and 1.41, respectively. Table 4 presents the
biodistribution data of the [18F]Q-4 compound in the S180-bearing mice. The uptake values of
[18F]Q-4 in the liver and kidney were both higher than those of [18F]Q-2, while the uptake value
of [18F]Q-4 in the tumour was lower than that of [18F]Q-2, which was supposed to be
metabolized by the liver and kidney. The high uptake value and target-to-nontarget ratio of
[18F]Q-2 at 15 min and 30 min indicated [18F]Q-2 to be suitable for imaging tumours at an early
stage.
Fig. 6. Biodistribution of [18F]Q-2 in mice bearing S180 tumours (column diagram).
Organs
Time (min)
60 min
15 min
30 min
120 min
Blood
Brain
Heart
Liver
3.13±0.40
1.32±0.26
3.24±0.17
13.55±1.00
2.47±0.23
1.09±0.06
2.03±0.08
5.73±0.77
2.21±0.15
1.08±0.06
2.04±0.19
4.48±0.25
1.41±0.08
0.91±0.04
1.66±0.02
2.61±0.52
14

Spleen
2.92±0.27
3.54±0.24
5.87±0.48
1.29±0.30
1.68±0.49
18.02±4.53
3.41±0.14
3.68±0.18
1.17
1.74±0.08
2.01±0.26
3.26±0.39
1.40±.032
1.60±0.15
12.7±2.16
1.98±0.27
2.25±0.10
0.91
1.54±0.04
1.89±0.24
2.15±0.08
1.38±0.17
1.90±0.26
15.6±2.12
2.31±0.90
2.32±0.13
1.04
1.01±0.10
1.34±0.25
1.36±0.08
1.23±0.22
3.70±0.81
7.09±1.62
1.69±0.80
1.83±0.07
1.29
Lung
Kidney
Muscle
Bone
Intestine
Stomach
Tumour
Tumour/Blood
Tumour/Muscle
Tumour/Bone
2.99
1.60
1.68
1.48
2.19
1.41
1.22
0.49
Table 3. Biodistribution of [18F]Q-2 (IC50 5.0 nM) in mice bearing S180 tumours after
intravenous injectiona.
a Data are expressed as the percentage of injected dose per gram (%ID/g), mean ± SD, n = 5.
Organs
Time (min)
60 min
15 min
30 min
120 min
Blood
2.71±0.29
1.33±0.17
1.49±0.19
10.77±2.08
2.30±0.35
2.01±0.42
5.85±0.64
0.82±0.07
1.04±0.39
21.08±4.88
4.09±0.54
2.03±0.10
0.75
2.79±0.45
1.52±0.17
2.42±0.41
8.69±1.87
2.51±0.77
2.20±0.76
6.88±2.62
1.39±.0.66
0.92±0.07
26.99±8.15
5.35±1.99
2.45±0.69
0.87
1.89±0.60
1.71±0.85
1.51±0.47
4.59±0.31
1.76±0.24
1.79±0.26
3.04±0.39
1.21±0.21
1.37±0.54
16.85±9.20
2.62±0.70
1.83±0.25
0.97
0.77±0.35
0.99±0.15
1.38±0.46
4.68±2.26
1.24±0.23
1.47±0.25
1.81±0.64
1.07±0.15
2.98±0.23
15.17±6.25
3.48±0.50
1.79±0.38
2.32
Brain
Heart
Liver
Spleen
Lung
Kidney
Muscle
Bone
Intestine
Stomach
Tumour
Tumour/Blood
Tumour/Muscle
2.48
1.76
1.51
1.67
15

Tumour/Bone
1.95
2.66
1.33
0.60
Table 4. Biodistribution of [18F]Q-4 (IC50 21.6 nM) in mice bearing S180 tumours after
intravenous injectiona.
a Data are expressed as the percentage of injected dose per gram (%ID/g), mean ± SD, n = 5.
In this study, a series of 2,4-diaminopyrimidine derivatives were synthesized and
characterized using 1H NMR, 13C HNMR, and HRMS spectra. The FAK-IC50 testing values were
5.0-205.1 nM. Among these compounds, [18F]Q-2 showed an obvious FAK kinase inhibition
effect, and its IC50 value was 5.0 nM. In addition, the [18F]Q-2 labelled by 18F demonstrated
promising biodistribution data in S180-bearing mice, with tumour/blood, tumour/muscle, and
tumour/bone ratios of 1.17, 2.99 and 2.19, respectively. Therefore, this compound might be a
potential PET imaging agent for tumour diagnosis.
Acknowledgements
This work was supported by the National Major Scientific and Technological Special Project for
“Significant New Drugs Development” (Grant Nos. 2014ZX09507007-001 and
2014ZX09507007-003) and the National Natural Science Foundation of China (Grant Nos.
21771022 and U1804188).
16

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Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
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