Discovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design

Article abstract of DOI:10.1021/acs.jmedchem.8b00057

Targeting KRAS-PDEδ protein-protein interactions with small molecules represents a promising opportunity for developing novel antitumor agents. However, current KRAS-PDEδ inhibitors are limited by poor cellular antitumor potency and the druggability of the target remains to be validated by new inhibitors. To tackle these challenges, herein, novel, highly potent KRAS-PDEδ inhibitors were identified by fragment-based drug design, providing promising lead compounds or chemical probes for investigating the biological functions and druggability of KRAS-PDEδ interaction.

Full text of DOI:10.1021/acs.jmedchem.8b00057

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Discovery of Novel KRAS-PDE# Inhibitors by Fragment-based Drug Design
Long Chen, Chunlin Zhuang, Junjie Lu, Yan Jiang, and Chunquan Sheng
J. Med. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Mar 2018
Downloaded from http://pubs.acs.org on March 6, 2018
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Journal of Medicinal Chemistry
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Discovery of Novel KRASꢀPDEδ Inhibitors by Fragmentꢀbased Drug
Design
Long Chen§, Chunlin Zhuang§, Junjie Lu§, Yan Jiang, Chunquan Sheng*
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School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China
Supporting Information
ABSTRACT: Targeting KRASꢀPDEδ proteinꢀprotein interactions with small molecules represents a promising opportunity for developꢀ
ing novel antitumor agents. However, current KRASꢀPDEδ inhibitors are limited by poor cellular antitumor potency, and the druggability
of the target remains to be validated by new inhibitors. To tackle these challenges, herein, novel, highly potent KRASꢀPDEδ inhibitors
were identified by fragmentꢀbased drug design, providing promising lead compounds or chemical probes for investigating the biological
functions and druggability of KRASꢀPDEδ interaction.
ing lead compounds or chemical probes for investigating the bioꢀ
logical functions and druggability of KRASꢀPDEδ interactions.
ꢀ
INTRODUCTION
Oncogenic KRAS signaling is an important antitumor pathway.1, 2
The KRAS protein is often mutated in different kinds of cancers
and especially in a large proportion (90%) of pancreatic cancers.3,
4
Targeting KRAS signaling is becoming an important field in
anticancer drug discovery and has achieved great success.5ꢀ9 Reꢀ
cently, inhibition of mammalian KRASꢀPDEδ proteinꢀprotein
interaction (PPI) by small molecules has been seen as a promising
opportunity for the discovery of novel antitumor agents.10ꢀ16
PDEδ, also named PDE6D, determines the KRAS dynamic distriꢀ
bution in the cell.17ꢀ19 The farnesylated KRAS protein is solubilꢀ
ized after binding with PDEδ, which enhances KRAS diffusion
18, 20, 21
throughout the cell.7,
After discharged from the PDEδ
binding pocket, the farnesylated KRAS is trapped by the recycling
endosome and then reꢀlocalized to the plasma membrane by veꢀ
sicular transport. Aberrant oncogenic signaling ultimately results
from the high concentration of KRAS at the plasma membrane.18,
22
Recently, Waldmann’s group reported pioneering works in the
discovery of smallꢀmolecule KRASꢀPDEδ inhibitors (Figure 1),
including benzimidazole inhibitor deltarasin (1),10 pyraꢀ
14
zolopyridazinone inhibitor deltazinone (2),11,
and
bis(sulfonamide) inhibitor deltasonamide (3).16 Compound 1 was
the first PDEδ inhibitor with nanomolar binding affinity; howevꢀ
er, it was a nonꢀselective inhibitor and showed apparent cytotoxiꢀ
city.10 Inhibitors 2 and 3 showed better selectivity toward PDEδ
than inhibitor 1, but they were limited by poor cellular antitumor
potency.15
Figure 1. Chemical structures of representative KRASꢀPDEδ
inhibitors.
ꢀ
RESULTS AND DISCUSSION
FBDD of KRASꢀPDEδ Inhibitors. Recently, our group identiꢀ
fied quinazolinone fragment hit 6 (Figure 2) as a novel KRASꢀ
PDEδ inhibitor (KD = 467 ± 65 nM) using a structureꢀbased virtuꢀ
al screening (SBVS).13 The crystal structure of the complex of
PDEδ with fragment 6 (PDB entry: 5X73) indicated that the two
molecules of inhibitor 6 bound to Arg61 and Tyr149 in the active
site mainly through hydrogenꢀbonding interactions (Figure 2A).
Similarly, Waldmann’s work revealed that two molecules of benꢀ
zimidazole fragment 7 (KD = 165 ± 23 nM, Figure 2) could also
bind in the two active sites (Figure 2C, PDB entry: 4JV6).10 Inꢀ
spired by these binding modes, computational FBDD28 was used
to rationally design novel PDEδ inhibitors by linking the two
fragmentꢀlike inhibitors. Based on molecular docking and interꢀ
molecular distance measurements, fragmentꢀlinking was proposed
at different sites on the two inhibitors. First, the distance from the
benzene ring of benzimidazole inhibitor 7 to the nitrogen atom of
Previously, our group reported novel bisꢀquinazolinone 4 and
quinazolinoneꢀpyrazolopyridazinone 5 as inhibitors based on a
virtual screening and structural biologyꢀguided drug design.13
Compound 5 exhibited excellent binding affinity (KD = 2 ± 0.5
nM) and moderate antitumor activity (IC50 = 18.6 ± 1.3 ꢁM)
against Capanꢀ1 pancreatic cancer cells.13 Nevertheless, its celluꢀ
lar potency needs improvement. Additionally, a new class of
KRASꢀPDEδ inhibitors is highly desirable to validate the druggaꢀ
bility of the target. Fragmentꢀbased drug design (FBDD) is
emerging as a powerful tool in drug discovery.23ꢀ27 In this study,
novel KRASꢀPDEδ inhibitors were identified using a FBDD stratꢀ
egy based on the coꢀcrystal complexes of fragmentꢀlike inhibitors
with PDEδ.10, 11, 13, 16 Interestingly, several new inhibitors showed
improved cellular antitumor activities, which makes them promisꢀ
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the amide in quinazolinone inhibitor 6 is 5.3 Å (Figure 2B). Seꢀ
7ꢀsubstituted derivatives (8eꢀ8g) were slightly lower than that of
8a. Among the prepared compounds, compound 8b, with a 6ꢀ
fluoro substituent, had the best PDEδ inhibitory activity (KD = 4.5
± 1.1 nM). However, compounds 8aꢀ8g showed no cellular antiꢀ
tumor activity toward Capanꢀ1 pancreatic cancer cells. The
ligand efficiency (LE)29 of the target compounds was also
calculated (Table S1 in Supporting Information). Moderate LE
of the fragmentꢀlike inhibitors 6 (LE= 0.08) and 7 (LE= 0.20) was
observed. After fragment linking, compounds 8aꢀg showed
improved LE (LE range: 0.23 ~ 0.31).
1
2
3
4
5
6
7
8
cond, the distance between the benzene ring of inhibitor 6 to the
imidazole nitrogen atom of inhibitor 7 is 5.0 Å (Figure 2D). Theꢀ
se distances were both suitable for using an ether linker between
the two methylenes. Thus, two series of compounds were deꢀ
signed and docked into the PDEδ protein. As shown in Figure 2E
and 2F, two representative compounds (8a and 9a) could insert
well into the binding pocket and form hydrogen bonds with Arg61
and Tyr149, mimicking the binding modes of the unlinked fragꢀ
mentꢀlike inhibitors 6 and 7 (Figure S1A and S1B in Supporting
Information). Although the predicted orientation of the benzimꢀ
idazole group in compounds 9a and 7 was flipped (Figure S1B
and S1C in Supporting Information), the hydrogenꢀbonding
interaction with Tyr149 was retained.
9
Table 1. Chemical structures, PDEδ binding affinities, and celluꢀ
lar level activities of compounds 8aꢀg.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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33
34
35
36
37
38
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
5.3 Å
O
N
F
O
N
R
r
e
k
n
N
i
L
N
N
F
H
N
N
N
H
8a-8g
PDEδ[a]
(KD, nM)
Capanꢀ1[b]
(IC50, ꢁM)
Compound
R
H
8a
8b
8c
8d
8e
8f
8g
2
9.0 ± 2.3
4.5 ± 1.1
11.6 ± 2.6
9.3 ± 2.5
12.1 ± 3.6
16.0 ± 3.4
9.8 ± 2.2
8 ± 3
> 100
> 100
6ꢀF
6ꢀCl
6ꢀCH3
7ꢀF
> 100
> 100
> 100
7ꢀCl
7ꢀOCH3
/
> 100
> 100
48 ± 6
18.6 ± 1.3
5
/
2 ± 0.5
[a]
[b]
Determined by fluorescence anisotropy assay. Determined by the CCK8 methꢀ
od.
When the position of the fragment linker was changed to the
quinazolinone N3ꢀphenyl group and the imidazole nitrogen atom,
the resulting compounds (9aꢀ9c) generally showed decreased
binding affinity (KD range: 146 ~ 192 nM), low LE (0.10 ~ 0.13,
Table S1) and no in vitro antitumor activity (Table 2). The reꢀ
moval of the benzene ring from the benzimidazole scaffold inꢀ
creased the binding affinity for PDEδ (compounds 9dꢀ9i, KD
range: 22 ~ 170 nM). Also, compounds 9d, 9e and 9g showed
improved LE (0.22 ~ 0.30, Table S1). The phenyl substitutions on
the imidazole ring were important for the inhibitory activity. For
example, methyl derivative 9e and unsubstituted derivative 9f
were less potent than the corresponding compounds with the pheꢀ
nyl substituents. To improve the water solubility, further pyriꢀ
dine/benzene replacement provided compounds 9gꢀ9i, which
showed similar activities. Among 9gꢀ9i, compound 9i possessed
moderate inhibitory activity against Capanꢀ1 cells (IC50 = 52 ± 2.5
ꢁM), which is comparable to that of compound 2 (IC50 = 48 ± 6
ꢁM).
Figure 2. Design of novel KRASꢀPDEδ inhibitors by a computaꢀ
tional FBDD strategy. (A) Coꢀcrystal structure of quinazolinone
fragment 6 with PDEδ protein (PDB entry: 5X73); (B) the first
fragmentꢀlinking strategy. (C) Coꢀcrystal structure of benzimidazꢀ
ole fragment 7 with PDEδ protein (PDB entry: 4JV6); (D) the
second fragmentꢀlinking strategy. (E) Proposed binding mode of
compound 8a with PDEδ protein; (F) proposed binding mode of
compound 9a with PDEδ protein. Yellow dashed lines represent
hydrogenꢀbonding interactions. Red dashed lines represent interꢀ
molecular distance measurements.
Biological Evaluations, Structureꢀactivity Relationship and
Binding Modes. Initially, fragmentꢀlike PDEδ inhibitors 6 and 7
were linked by an ethyl ether (–(CH2)2Oꢀ) linker, and pyriꢀ
dine/benzene replacement was used to improve the water solubiliꢀ
ty. Based on these structural features, compound 8a was syntheꢀ
sized and assayed. Compared to inhibitors 6 and 7, compound 8a
(KD = 9.0 ± 2.3 nM) showed improved PDEδ inhibitory activity,
and its activity was comparable to that of compound 2 (KD = 8 ± 3
nM). When substituents were introduced at the 6 position of the
quinazolinone scaffold, the resulting compounds (8bꢀ8d, KD
range: 4.5 ~ 11.6 nM) showed superior or comparable binding
affinities to that of compound 8a. In contrast, the activities of the
Table 2. Structures, PDEδ binding affinities, and cellular level
activities of compounds 9aꢀi designed by the fragmentꢀlinking
strategy.
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Journal of Medicinal Chemistry
spectively. In particular, compound 11b showed good antitumor
O
O
N
1
2
3
4
5
6
7
8
activity (Capanꢀ1, IC50 = 8.8 ± 2.4 ꢁM), and it was more potent
than compound 2 (Capanꢀ1, IC50 = 48 ± 6 ꢁM) and quinazolinone
inhibitor 5 (Capanꢀ1, IC50 = 18.6 ± 1.3 ꢁM). When bulkier
groups, namely, cyclobutyl (11c), cyclopentyl (11d) and cycloꢀ
hexyl (11e), were introduced, their PDEδ inhibitory activities and
cytotoxicities were lower probably due to steric hindrance. Quanꢀ
titative activityꢀactivity relationships (QAAR)30 analysis indicated
that there was good positive correlation (R2 = 0.62, Figure S2 in
Supporting Information) between the inhibitory activity against
PDEδ and Capanꢀ1 cells. Furthermore, the binding mode of comꢀ
pounds 10g and 11b was investigated by molecular docking studꢀ
ies. As shown in Figure 3B, the binding mode of compound 11b
was similar to that of compound 10g. The cyclopropyl group of
11b formed additional hydrophobic interactions with Ile129,
Val145 and Leu147. Finally, compound 11b had a good combinaꢀ
tion of PDEδ binding affinity (KD = 38 ± 17 nM) and cytotoxicity
(IC50 = 8.8 ± 2.4 ꢁM) and was therefore subjected to further bioꢀ
logical evaluations.
N
N
N
N
R
R
O
N
5.0 Å
N
H
Ar
Ar
9a-9c
N
Linker
N
HN
F
O
O
N
N
H
9f-9i
Comꢀ
pound
PDEδ[a]
(KD, nM)
Capanꢀ1[b]
(IC50, ꢁM)
Ar
R
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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42
43
44
45
46
47
48
49
50
51
52
53
54
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56
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58
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60
9a
9b
9c
9d
9e
9f
9g
9h
9i
2ꢀFꢀPh
2ꢀFꢀPh
Ph
CH3
Ph
Ph
CH3
H
168 ± 25
146 ± 22
192 ± 35
29 ± 11
53 ± 19
80 ± 15
22 ± 8
> 100
> 100
pyridinꢀ2ꢀyl
2ꢀFꢀPh
> 100
> 100
2ꢀFꢀPh
> 100
Table 3. Structures, PDEδ binding affinities, and cellular level
activities of compounds 10aꢀg and 11aꢀe.
2ꢀFꢀPh
> 100
N
N
O
N
N
O
pyridinꢀ2ꢀyl
pyridinꢀ2ꢀyl
pyridinꢀ2ꢀyl
/
Ph
CH3
H
52 ± 2.5
> 100
N
F
N
N
N
R
166 ± 33
170 ± 28
8 ± 3
N
H
N
> 100
R'
F
F
10a-10g
11a-11e
2
/
48 ± 6
18.6 ± 1.3
5
/
/
2 ± 0.5
Comꢀ
pound
PDEδ[a]
(KD, nM)
Capanꢀ1[b]
(IC50, ꢁM)
R
R’
[a]
[b]
Determined by fluorescence anisotropy assay. Determined by the CCK8 methꢀ
od.
10a
10b
10c
10d
10e
10f
H
6ꢀCH3
6ꢀOCH3
7ꢀCH3
7ꢀOCH3
7ꢀF
H
H
H
H
H
H
H
67 ± 24
56 ± 26
146 ± 51
105 ± 33
167 ± 45
101 ± 34
85 ± 27
37 ± 22
38 ± 17
34 ± 3.4
42 ± 3.9
74 ± 6.5
78 ± 7.2
82 ± 6.4
35 ± 3.2
33 ± 2.9
47 ± 8.4
8.8 ± 2.4
Inspired by our previously identified quinazolinone inhibitors (4
and 5),13 the phenyl group in compound 9f was replaced by a
piperidinyl group. Interestingly, resulting compound 10a showed
improved cellular activity (Capanꢀ1, IC50 = 34 ± 3.4 ꢁM). Howꢀ
ever, further introduction of substituents on the quinazolinone
scaffold did not have positive effects on the cytotoxicity. Subseꢀ
quently, molecular docking studies indicated that compound 10g
could insert well into the two binding pockets of PDEδ and form
hydrogen bonds with both Arg61 and Glu88 (Figure 3A).
10g
11a
11b
6ꢀF
H
ꢀCH3
H
11c
11d
H
H
50 ± 25
60 ± 31
11.6 ± 3.8
12.4 ± 4.3
11e
2
H
/
81 ± 30
8 ± 3
54.6 ± 7.6
48 ± 6
/
/
5
/
2 ± 0.5
18.6 ± 1.3
[a]
[b]
Determined by fluorescence anisotropy assay. Determined by the CCK8 methꢀ
od.
Compound 11b Inhibited the Phosphorylation of Akt and Erk
in Capanꢀ1 Cells. The RAS family regulates the MAPK and
PI3KꢀAktꢀmTOR pathways4 and influences cell growth, proliferaꢀ
tion, and differentiation.6 Thus, the effects of the most potent
compound (11b) on the phosphorylation of extracellular signalꢀ
regulated kinase (Erk) and protein kinase B/Akt were evaluated.
The epidermal growth factor (EGF) was used to induce the exꢀ
pression of MAPK and Akt.13 Phosphorylation levels of Erk and
Akt were determined using Capanꢀ1 cells unstimulated and stimuꢀ
lated with EGF and then treated with compounds 11b or 2 for 1 h
(Figure 4). When unstimulated cells were treated with compound
Figure 3. Proposed binding mode of compounds 10g (A) and 11b
(B) with PDEδ.
Notably, there was a small hydrophobic pocket around the
quinazolinone NH and no hydrogenꢀbonding interaction was obꢀ
served, suggesting that the incorporation a suitable hydrophobic
group improved the binding affinity. Thus, as expected, when
methyl and cycloalkyl groups were introduced, the resulting comꢀ
pounds (11a and 11b, respectively) showed improved PDEδ inꢀ
hibitory activities (KD = 37 ± 22 nM and KD = 38 ± 17 nM), reꢀ
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2 (10 ꢁM), no differences were observed in Akt and Erk phosꢀ
membrane, and compound 2 was less potent at the same concenꢀ
1
2
3
4
5
6
7
8
phorylation. When compound 11b (10 ꢁM) was used, Akt phosꢀ
phorylation was downregulated, but there was no effect on Erk
phosphorylation. At 20 ꢁM, compound 2 significantly decreased
Akt phosphorylation and slightly decreased Erk phosphorylation.
The phosphorylation of both Akt and Erk was dramatically reꢀ
duced by treatment with compound 11b at the same dose. When
EGFꢀstimulated cells were treated with compound 2, there was no
change in the phosphorylation of Akt, but the phosphorylation of
Erk decreased in a doseꢀdependent manner. In contrast, treatment
with compound 11b significantly downregulated the phosphorylaꢀ
tion of both Akt and Erk.
tration (20 ꢁM).
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12
13
14
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Figure 5. (A) Apoptosis in the Capanꢀ1 cell line induced by 48 h
of treatment with compound 2 (50 ꢁM) and compound 11b (10
ꢁM and 25 ꢁM). (B) Immunostaining of Capanꢀ1 with antiꢀpanꢀ
RAS (red) and antiꢀPDEδ (green) after treatment with various
compounds for 2 h (2, 20 ꢁM; 11b, 20 ꢁM). The vehicle control
for the above experiments was 0.1% DMSO. (∗∗∗) p < 0.001.
ꢀ
CONCLUSION
In summary, novel quinazolinoneꢀimidazole KRASꢀPDEδ inhibiꢀ
tors were successfully identified by FBDD. All the target comꢀ
pounds showed nanomolar inhibitory activity toward PDEδ, conꢀ
firming the power of FBDD in drug discovery. Compound 11b
had a good combination of binding affinity and antitumor activity.
In Capanꢀ1 cells, 11b significantly induced apoptosis, downreguꢀ
lated EGFꢀinduced Erk and Akt phosphorylation, and induced the
distribution of endogenous RAS to the endomembranes. The lack
of cellular potency is the major limitation of current KRASꢀPDEδ
inhibitors, and 11b showed more potent antitumor activity than
pyrazolopyridazinone and quinazolinone inhibitors. Thus, this
molecule is a promising lead compound for investigating the bioꢀ
logical functions and druggability of KRASꢀPDEδ PPI. Further
lead optimization studies are in progress.
Figure 4. (A) Phosphorylation levels of Erk and Akt using oncoꢀ
genic KRASꢀdependent Capanꢀ1 cells that were unstimulated or
stimulated with EGF (125 ng/mL, 5 min). From top to bottom:
phosphorylated Akt on S473 (pꢀAkt), total level of Akt1 (tꢀAkt1),
phosphorylated Erk on Thr202 and Tyr204 (pꢀErk), total level of
Erk (tꢀErk), and loading control (GAPDH). (B) Gray intensity
analysis of the Western blots in which the quantification of pꢀ
Erk/tꢀErk ± SEM (left) and pꢀAkt/tꢀAkt ± SEM (right) was norꢀ
malized to the EGFꢀstimulated control (0.1% DMSO). (∗) p<0.05,
(∗∗) p<0.01, (∗∗∗) p<0.001. EGF, epidermal growth factor.
ꢀ
EXPERIMENTAL SECTION
Compound 11b Induced Apoptosis and Distribution of Enꢀ
dogenous RAS to Endomembrane in Capanꢀ1 Cells. The cell
apoptosis assay indicated that compound 2 (50 ꢁM) induced apopꢀ
tosis at a rate of 20.50% (Figure 5A and 5B). In contrast, comꢀ
pound 11b induced apoptosis in 17.95% and 36.40% of the cells
at 10 and 25 ꢁM, respectively. 11b induced apoptosis in a doseꢀ
dependent manner and was more potent than compound 2 even at
a lower dose. Immunofluorescence staining was used to evaluate
the RAS distribution in Capanꢀ1 cells (Figure 5C). Compound
11b induced the distribution of endogenous RAS to the endoꢀ
General. All the reagents and solvents were analytically pure and
were used as received from the vendors. TLC analysis was carried
out on silica gel plates GF254 (Qindao Haiyang Chemical, China).
Silica gel chromatography was carried out on 300ꢀ400 mesh gel.
The anhydrous solvents and reagents were dried by routine protoꢀ
cols. NMR spectra were recorded on Bruker Avance 600 specꢀ
trometers (Bruker Company, Germany) using TMS as an internal
standard and CDCl3 or DMSOꢀd6 as the solvents. The chemical
shifts (δ values) and coupling constants (J values) are given in
ppm and Hz, respectively. The melting points were measured on a
WRR digital melting point apparatus (Shanghai Jingke Instrument;
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Journal of Medicinal Chemistry
China). The mass spectra were recorded on an APIꢀ3000 LCꢀMS
2ꢀ(2ꢀFluorophenyl)ꢀ3ꢀ(2ꢀ(4ꢀ(1ꢀ(pyridinꢀ4ꢀylmethyl)ꢀ1Hꢀbenzoꢀ
[d]imidazoleꢀ2ꢀyl)phenoxy)ethyl)ꢀ2,3ꢀdihydroquinazolinꢀ4(1H)
ꢀone (8a). Yellow solid, yield 53.1%, m.p.: 154ꢀ159 °C; 1H NMR
(600 MHz, DMSOꢀd6) δ 8.45 (d, 2H, J = 4.39 Hz), 7.84 (t, 2H, J
= 8.78 Hz), 7.56 (d, 2H, J = 8.38 Hz), 7.39 (d, 1H, J = 7.98 Hz),
7.30 (s, 2H), 7.17ꢀ7.24 (m, 5H), 7.06ꢀ7.08 (m, 1H), 6.94ꢀ6.97 (m,
4H), 6.64ꢀ6.68 (m, 2H), 6.31 (s, 1H), 5.56 (s, 2H), 4.17ꢀ4.20 (m,
1H), 4.09ꢀ4.14 (m, 2H), 3.24ꢀ3.28 (m, 1H); 13C NMR (150 MHz,
DMSOꢀd6) δ 164.65, 162.22, 161.17, 160.59, 155.08, 151.91,
147.90, 147.88, 144.55, 137.72, 135.38, 132.41, 132.36, 132.29,
129.58, 129.49, 129.31, 129.23, 126.36, 124.49, 124.18, 124.12,
123.03, 121.03, 119.18, 117.92, 117.78, 116.55, 116.29, 116.16,
112.60, 67.72, 67.61, 48.47, 45.53; MS (ESI+): m/z calcd for
C35H28FN5O2 569.22, found 570.69 [M+H]+.
mass spectrometer. The purities of the compounds were deterꢀ
mined by HPLC (Agilent 1260), and all final compounds exhibitꢀ
ed purities greater than 95%.
1
2
3
4
5
6
7
8
General Procedure A. The Synthesis of Compounds 8. As
described in Scheme S1 in the Supporting Information, intermeꢀ
diate m3 (190 mg, 0.52 mmol) and 10% PdꢀC were combined in
MeOH (10 mL) under a H2 atmosphere and stirred at room temꢀ
perature overnight. The reaction mixture was filtered through
Celite, and the filtrate was concentrated under reduced pressure to
afford crude product m4, which was used directly in the next step
without purification. Crude m4 was dissolved in DMF (5 mL) and
treated with HBTU (300 mg, 0.78 mmol), TEA (160 mg, 1.56
mmol), and the substituted 2ꢀaminobenzoic acid (0.52 mmol) at
room temperature for 12 h. The mixture was poured into water
(100 mL) to precipitate the product as a white solid. The solid was
isolated by filtration, dissolved in acetic acid (5 mL), and then
treated with 2ꢀfluorobenzaldehyde (130 mg, 1.04 mmol) under
reflux for 4 h. The mixture was poured into water (50 mL) and
extracted with EtOAc (3 × 30 mL). The combined organic phases
were dried and concentrated under reduced pressure. The crude
product was purified by column chromatography (DCM/MeOH =
100:2) to give target compounds 8aꢀ8g.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀ(2ꢀFluorophenyl)ꢀ3ꢀ(4ꢀ(2ꢀ(2ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ1ꢀ
yl)ethoxy) phenyl)ꢀ2,3ꢀdihydroquina zolinꢀ4(1H)ꢀone (9a). Pale
solid, yield 33.6%, m.p.: 185ꢀ191 °C; 1H NMR (600 MHz,
DMSOꢀd6) δ 7.97 (d, 1H, J = 8.6 Hz), 7.89 (d, 2H, J = 7.1 Hz),
7.77 (d, 1H, J = 7.7 Hz), 7.70 (d, 1H, J = 8.1 Hz), 7.64ꢀ7.65 (m,
3H), 7.40ꢀ7.50 (m, 4H), 7.25ꢀ7.31 (m, 2H), 7.08ꢀ7.12 (m, 2H),
7.06 (d, 2H, J = 9.1 Hz), 6.71ꢀ6.74 (m, 2H), 6.68 (d, 2H, J = 8.7
Hz), 6.40 (s, 1H), 4.75 (t, 2H, J = 4.8 Hz), 4.29 (t, 2H, J = 4.8 Hz);
13C NMR (150 MHz, DMSOꢀd6) δ 163.53, 161.33, 159.69, 157.18,
153.61, 147.75, 135.13, 135.01, 134.64, 132.52, 131.97, 131.92,
131.29, 130.27, 129.67, 129.44, 129.10, 128.57, 128.48, 125.77,
125.65, 118.80, 117.96, 117.10, 116.96, 115.86, 115.82, 115.53,
114.00, 69.18, 66.93, 45.82; MS (ESI+): m/z calcd for
C35H27FN4O2 554.21, found 555.58 [M+H]+.
General Procedure B. The Synthesis of Compounds 9. As deꢀ
scribed in Scheme S2 in the Supporting Information, a solution of
m12 or m13 (0.6 mmol), the corresponding intermediate from
m19ꢀm23 (0.6 mmol), and triphenylphosphine (0.32 g, 1.2 mmol)
were stirred in dry toluene (10 mL) at 0 °C under a nitrogen atꢀ
mosphere. TMAD was added to this mixture (0.21 g, 1.2 mmol) in
dry toluene (5 mL) over a period of 5 min. The resulting suspenꢀ
sion was heated for 48 h at 65 °C. The solvent was evaporated
under reduced pressure, and the residue was diluted with EtOAc
(50 mL) and washed with saturated sodium bicarbonate solution
(2 × 30 mL). The aqueous phase was reꢀextracted with EtOAc (30
mL). The combined organic phases were dried, filtered and conꢀ
centrated under reduced pressure. The crude product was purified
by column chromatography (DCM/MeOH = 100:1 to 100:5) to
give target molecules 9aꢀ9i.
6ꢀFluoroꢀ2ꢀ(2ꢀfluorophenyl)ꢀ3ꢀ(1ꢀ(3ꢀ(2ꢀphenylꢀ1Hꢀimidazolꢀ1ꢀ
yl)propyl)piperidinꢀ4ꢀyl)ꢀ2,3ꢀdihydroquinazolinꢀ4(1H)ꢀone
1
(10g). White solid, yield 37.2%, m.p.: 172ꢀ174 °C; H NMR (600
MHz, DMSOꢀd6) δ 7.57ꢀ7.58 (m, 2H), 7.33ꢀ7.41 (m, 5H), 7.26ꢀ
7.29 (m, 3H), 7.05ꢀ7.15 (m, 3H), 6.97 (d, 1H, J = 1.0 Hz), 6.70
(dd, 1H, J = 4.6, 8.8 Hz), 6.07 (d, 1H, J = 3.4 Hz), 4.27ꢀ4.32 (m,
1H), 4.03 (t, 2H, J = 7.1 Hz), 2.73 (d, 1H, J = 10.7 Hz), 2.57 (d,
1H, J = 10.7 Hz), 2.05ꢀ2.13 (m, 2H), 1.85 (t, 1H, J = 10.5 Hz),
1.68ꢀ1.77 (m, 4H), 1.52ꢀ1.54 (m, 1H), 1.26 (d, 1H, J = 12.0 Hz),
1.05ꢀ1.12 (m, 1H); 13C NMR (150 MHz, DMSOꢀd6) δ 161.62,
159.95, 158.33, 156.18, 154.63, 147.07, 142.18, 131.68, 130.84,
130.79, 129.45, 129.36, 129.01, 128.76, 128.66, 128.38, 127.75,
124.65, 121.84, 121.21, 121.05, 117.07, 117.03, 116.44, 116.30,
113.25, 113.09, 61.06, 54.12, 53.10, 52.63, 51.92, 44.47, 29.80,
29.73, 28.17; MS (ESI+): m/z calcd for C31H31F2N5O 527.25,
found 528.77 [M+H]+.
General Procedure C. The Synthesis of Compounds 10. As
described in Scheme S3 in the Supporting Information, a mixture
of m33ꢀm39 (0.66 mmol) and 20% Pd(OH)2 in MeOH (10 mL)
was stirred under a H2 atmosphere at room temperature overnight.
Then, the mixture was filtered through Celite, and the filtrate was
concentrated under reduced pressure to afford the crude product
without purification. Then, the crude product was dissolved in
acetonitrile (15 mL). The solution was combined with m25 (300
mg, 1.32 mmol), K2CO3 (364 mg, 2.64 mmol) and KI (11 mg,
0.07 mmol) and refluxed for 12 h. The mixture was poured into
water (50 mL) and extracted with EtOAc (2 × 30 mL). The comꢀ
bined organic phases were dried and then concentrated under
reduced pressure. The crude product was purified by column
chromatography (DCM/MeOH = 40:1) to afford 10aꢀ10g.
1ꢀ(Cyclopropylmethyl)ꢀ6ꢀfluoroꢀ2ꢀ(2ꢀfluorophenyl)ꢀ3ꢀ(1ꢀ(3ꢀ(2ꢀ
phenylꢀ1Hꢀimidazolꢀ1ꢀyl)propyl)piperidinꢀ4ꢀyl)ꢀ2,3ꢀdihydroꢀ
quinazolinꢀ4(1H)ꢀone (11b). White solid, yield 50.8%, m.p.:
1
135ꢀ139 °C. HꢀNMR (600 MHz, DMSOꢀd6) δ 7.57 (d, 2H, J =
6.9 Hz), 7.50 (dd, 1H, J = 3.1, 8.9 Hz), 7.30ꢀ7.38 (m, 5H), 7.24
(dd, 1H, J = 8.2, 10.2 Hz), 7.16ꢀ7.19 (m, 1H), 7.03ꢀ7.05 (m, 2H),
6.97 (s, 1H), 6.90ꢀ6.92 (m, 1H), 6.13 (s, 1H), 4.27ꢀ4.31 (m, 1H),
3.99ꢀ4.06 (m, 2H), 3.42ꢀ3.45 (m, 1H), 3.15ꢀ3.19 (m, 1H), 2.79 (d,
1H, J = 9.1 Hz), 2.61 (d, 1H, J = 9.1 Hz), 2.11ꢀ2.16 (m, 2H), 1.84ꢀ
1.89 (m, 2H), 1.73ꢀ1.78 (m, 3H), 1.59 (d, 1H, J = 8.4 Hz), 1.24ꢀ
1.28 (m, 1H), 1.09ꢀ1.18 (m, 2H), 0.44ꢀ0.58 (m, 2H), 0.27ꢀ0.30 (m,
1H), 0.16ꢀ0.19 (m, 1H). 13C NMR (150 MHz, DMSOꢀd6) δ
161.37, 160.19, 158.56, 157.07, 155.50, 146.98, 142.02, 131.54,
130.86, 130.80, 128.96, 128.74, 128.64, 128.29, 127.99, 127.85,
127.76, 124.59, 121.89, 121.47, 121.42, 120.92, 120.76, 119.76,
119.71, 116.43, 116.29, 113.48, 113.32, 66.44, 56.27, 54.24,
53.00, 52.75, 52.22, 44.57, 29.72, 29.59, 29.42, 28.11. MS (ESI+):
m/z calc. for [M+H]+ C35H37F2N5O: 582.30, found: 582.55.
General Procedure D. The Synthesis of Compounds 11. As
described in Scheme S3 in the Supporting Information, to a soluꢀ
tion of 10g (0.22 g, 0.42 mmol) in DMF (4 mL) was added NaH
(60%, 30 mg, 0.63 mmol) slowly at 0 °C over 0.5 h. Then, the
brominated alkane (0.84 mmol) in DMF (1 mL) was added dropꢀ
wise. The reaction mixture was stirred at room temperature for
another 2 h and was then poured into water (50 mL) and extracted
with EtOAc (3 × 30 mL). The combined organic phases were
washed with water (2 × 30 mL) and brine (30 mL), dried and then
concentrated under reduced pressure. The crude product was puriꢀ
fied by column chromatography (hexane/EtOAc = 2:1) to afford
compounds 11aꢀ11e. (45%ꢀ63% yield).
ASSOCIATED CONTENT
Supporting Information
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Journal of Medicinal Chemistry
Page 6 of 7
Bind to A Distinct Pocket in Ras and Inhibit SOSꢀMediated Nucleotide
The Supporting Information is available free of charge on the
ACS Publications website.
Exchange Activity. Proc. Natl. Acad. Sci. U S A 2012, 109, 5299ꢀ5304.
6. Berndt, N.; Hamilton, A. D.; Sebti, S. M. Targeting Protein Prenylation
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Gremer, L.; Triola, G.; Waldmann, H.; Bastiaens, P. I.; Wittinghofer, A.
Arl2ꢀGTP and Arl3ꢀGTP Regulate a GDIꢀlike Transport System for Farꢀ
nesylated Cargo. Nat. Chem. Biol. 2011, 7, 942ꢀ949.
1
2
3
4
Synthetic protocols, detailed experimental procedures,
1
QAAR graph, LE calculation and H and 13C NMR spectra
of target compounds. (DOCX)
5
SMILES Molecular formula strings (CSV).
6
7
8
9
8. Bournet, B.; Buscail, C.; Muscari, F.; Cordelier, P.; Buscail, L. Targetꢀ
ing KRAS for Diagnosis, Prognosis, and Treatment of Pancreatic Cancer:
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son, A. G.; Lee, T.; Rossanese, O. W.; Fesik, S. W. Discovery of Small
Molecules that Bind to KꢀRas and Inhibit SosꢀMediated Activation. Anꢀ
gew. Chem., Int. Ed. 2012, 51, 6140ꢀ6143.
AUTHOR INFORMATION
Corresponding Author
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*Eꢀmail: shengcq@smmu.edu.cn.
10. Zimmermann, G.; Papke, B.; Ismail, S.; Vartak, N.; Chandra, A.;
Hoffmann, M.; Hahn, S. A.; Triola, G.; Wittinghofer, A.; Bastiaens, P. I.;
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zolopyridazinones as PDEdelta Inhibitors. Nat. Commun. 2016, 7, 11360.
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Ismail, S.; Triola, G.; Nussbaumer, P.; Wittinghofer, A.; Waldmann, H.
Structure Guided Design and Kinetic Analysis of Highly Potent Benzimꢀ
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Chem. 2014, 57, 5435ꢀ5448.
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Li, J.; Sheng, C. Structural BiologyꢀInspired Discovery of Novel KRASꢀ
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ORCID
Chunlin Zhuang: 0000ꢀ0002ꢀ0569ꢀ5708
Chunquan Sheng: 0000ꢀ0001ꢀ9489ꢀ804X
Author Contributions
§ These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Founꢀ
dation of China (Grants 21738002 and 81725020 to C. S.) and the
“Young Elite Scientists Sponsorship” from the China Association
for Science and Technology (C. Z.).
ABBREVIATIONS USED
FBDD
PPI
SBVS
LE
Erk
EGF
HBTU
fragmentꢀbased drug design
proteinꢀprotein interaction
structureꢀbased virtual screening
ligand efficiency
extracellular signalꢀregulated kinase
epidermal growth factor
OꢀbenzotriazoleꢀN,N,N',N'ꢀtetraMethylꢀ
uroniumꢀhexafluorophosphate
TMAD
dicarboxamide
QAAR
N,N,N',N'ꢀtetramethyldiazeneꢀ1,2ꢀ
quantitative activityꢀactivity relationships
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Graphic Abstract
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