Development and structure-activity relationship study of SHP2 inhibitor containing 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene

Article abstract of DOI:10.1016/j.bmcl.2019.126756

SHP2, a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene, plays an important role in the cell growth and proliferation. Activating mutations of SHP2 have been reported as a cause of various human diseases such as solid tumors, leukemia, and Noonan syndrome. The discovery of SHP2 inhibitor can be a potent candidate for the treatment of cancers and SHP2 related human diseases. Several reports on a small molecule targeting SHP2 have published, however, there are limitations on the discovery of SHP2 phosphatase inhibitors due to the polar catalytic site environment. Allosteric inhibitor can be an alternative to catalytic site inhibitors. 3,4,6-Trihydroxy-5-oxo-5H-benzo[7]annulene 1 was obtained as an initial hit with a 0.097 μM of IC₅₀ from high-throughput screening (HTS) study. After the structure-activity relationship (SAR) study, compound 1 still showed the most potent activity against SHP2. Moreover, compound 1 exerted good potency against SHP2 expressing 2D and 3D MDA-MB-468.

Full text of DOI:10.1016/j.bmcl.2019.126756

Journal Pre-proofs
Development and structure-activity relationship study of SHP2 inhibitor con-
taining 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene
Bohee Kim, Seungjin Jo, Sung Bum Park, Chong Hak Chae, Kwangho Lee,
Byumseok Koh, Inji Shin
PII:
S0960-894X(19)30719-X
https://doi.org/10.1016/j.bmcl.2019.126756
BMCL 126756
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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10 October 2019
13 October 2019
Please cite this article as: Kim, B., Jo, S., Park, S.B., Chae, C.H., Lee, K., Koh, B., Shin, I., Development and
structure-activity relationship study of SHP2 inhibitor containing 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene,
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Bioorganic & Medicinal Chemistry Letters
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Development and structure-activity relationship study of SHP2 inhibitor
containing 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene
Bohee Kim, b,d,¶ Seungjin Jo, b,c,¶ Sung Bum Park,b Chong Hak Chae,b Kwangho Lee,b,c Byumseok Kohb,*
and Inji Shina,b,c
*
a Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, 01811 South Korea
b Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114 South Korea
cMedicinal Chemistry & Pharmacology, Korea University of Science & Technology, Daejeon, 34113 South Korea
dDepartment of Chemistry, Chungnam University, Daejeon, 28644 South Korea
¶B.K. and S.J. contributed equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
SHP2, a non-receptor protein tyrosine phosphatase encoded by PTPN11 gene, plays an
important role in the cell growth and proliferation. Activating mutations of SHP2 have been
reported as a cause of various human diseases such as solid tumors, leukemia, and Noonan
syndrome. The discovery of SHP2 inhibitor can be a potent candidate for the treatment of
cancers and SHP2 related human diseases. Several reports on a small molecule targeting SHP2
have published, however, there are limitations on discovery of SHP2 phosphatase inhibitors due
to the polar catalytic site environment. Allosteric inhibitor can be an alternative to catalytic site
inhibitors. 3,4,6-trihydroxy-5-oxo-5H-benzo[7]annulene 1 was obtained as an initial hit with
a 0.097 μ M of IC50 from high-throughput screening (HTS) study. After the structure-
activity relationship (SAR) study, compound 1 still showed the most potent activity against
SHP2. Moreover, 1 and 2j exerted good potency against SHP2 expressing 2D and 3D MDA-
MB468.
Keywords:
SHP2
PNPN11
Protein tyrosine phosphatase
inhibitor
SAR
2009 Elsevier Ltd. All rights reserved.
SHP2 is a PTPN11 gene encoded non-receptor protein
tyrosine phosphatase,1
and regulates cell survival and
proliferation through activation of the RAS-ERK.2,3,4,5,6 It has
been suggested that SHP2 interacts with growth factor receptor-
bound protein 2 (GRB2) associated binding protein 1 (GAB1),
which participates in signal transducer and STAT1 regulation.7

SHP2 also known to promotes signal transduction of human
epidermal growth factor receptor 2 (HER2) to control tumor
development. Activating mutations of SHP2 have been
associated in various human diseases, such as several types of
leukemia,8 solid tumors, such as lung, colon, and prostate
cancers,9,10,11 and Noonan syndrome.12
from Korea Chemical Bank including the libraries of phosphatase,
clinically active compounds and natural compounds. 214
chemicals showed more than 50% inhibition of SHP2 at
concentration of 1 μM. After further SHP2 assay screening,
three compounds had reliable inhibition activities repeatedly
with greater than 90% inhibition at concentration of 1 μM.
Among them compound 1 with 3,4,6-trihydroxy-5-oxo-5H-
benzo[7]annulene as a core structure showed the most potent
SHP2 inhibition with a 0.097 μM of IC50 value (Figure 2). The
other two compounds are under investigation, so we will not
discuss these compounds in this paper including chemical
structures.
Figure 1. Examples of small molecule allosteric- and active-site SHP2
inhibitors
Moreover SHP2 has been reported to bind to immune-inhibitory
receptors and participate in the
T cell programed cell
death/checkpoint pathway (PD-L1/PD-1).13 SHP2 is known to
engage with PD-1, contributing to T cell exhaustion.14 Anti-PD-1
treatment together with SHP2 deficient T cells shown to be
beneficial in treating cancer in vivo.
To confirm the activity, we planned to synthesize 1.
Representative synthetic route is outlined in Scheme 1.
Compound 1 is successfully prepared from the corresponding
catechol and trihydroxybenzoic acid in presence of KIO3. The
inhibition activity of 1 against SHP2 was tested under the same
biochemical assay system, and IC50 of 0.097 μM was
repeatedly obtained.
SHP2 consists of two consecutive phosphotyrosine binding
domains (N-SH2 and C-SH2), one catalytic PTP domain, and C-
terminal tail. SHP2 stays as an auto-inhibited conformation by
intramolecular interactions of N-SH2 domain and PTP domain.
However this auto-inhibition is disrupted by binding of
bisphosphotyrosyl proteins to SH2 domains, and SHP2 becomes
active conformation.15,16,17
Several research groups have reported small molecules which
are active-site SHP2 inhibitors binding to catalytic PTP domain
directly, however, these inhibitors show low potency and poor
pharmaceutical properties. Due to the polar nature of the catalytic
site of PTPs, the discovery of an active-site targeting small
molecule have been challenged.18,19,20,21 Allosteric inhibition may
be a good alternative to overcome the limitations of the PTP
catalytic inhibitors. Recently several research groups reported
SHP2 allosteric inhibitors,22,23 SHP09924,25,26, SHP244,27 and
RMC-4550.28 These studies show promising development of
allosteric PTP inhibitors targeting SHP2 which are potent and
orally bioavailable. However, these SHP2 inhibitor candidates
show relatively weak anti-cancer potency against cancer cells
compare to other potent reagents. This motivates us to search for
a more potent SHP2 inhibitor with better anticancer efficacy.
Scheme 1. Synthetic route for the preparation of 1.
As structure-activity relationship study, we designed and
synthesized
various
3,4,6-trihydroxy-5-oxo-5H-
benzo[7]annulene derivatives. Compounds 2a–2n with
a
variety of substituents on rings were prepared through the
same or modified synthetic pathway using corresponding
starting materials (Scheme 1 and see supporting information)
and evaluated SHP2 inhibition (Table 1).
First, carboxylic acid was masked with various alkyl
groups, such as a methyl, ethyl or isopropyl, to transfer to
esters (2a-2c, entries 2-4). Methyl ester 2a gave 87%
inhibition with IC50 of 0.161 μM, but other alkyl esters, 2b and
2c, did not show good inhibition values. Amide 2d was also
tested, but it only showed 13% inhibition of SHP2. Instead of
carbonyl moieties, compounds with a nitrile or an oxazole
were also prepared and evaluated, however, they were a lot
less potent than 1 (2e and 2g, entries 6 and 8). If carboxylic
acid was removed, inhibition of SHP2 was not detected at all
(2f, entry 7). To explore the scope further, compounds with an
additional substituent, such as OMe or F, on a left-side ring
were synthesized (entries 9-15). The derivatives with a
methoxy group showed almost no inhibition activities against
SHP2 (2h and 2i, entries 9 and 10). Compound 2j which has a
fluorine on R1 position and a carboxylic acid on R2 positon
gave a comparable SHP2 activity, a 90% SHP2 inhibition and
0.277 μM of IC50, to compound 1 (2j, entry 11). All the other
analogues with a fluorine, however, gave lower inhibition
activities (2k-2n, entries 12-15).
Herein we report the discovery of a SHP2 inhibitor through
high-throughput screening and structure-activity relationship
study. Moreover we further tested efficacy as a SHP2 inhibitor
with selected compounds.
To examine the role of alcohols as hydrogen bonding
interactions, all hydroxyl groups of 1 and 2a were protected
with methyl groups to generate methylated compounds, 3a and
3b, respectively (Table 2). Unfortunately SHP2 inhibitions
were lost under the same biochemical assay conditions. After
the structure-activity relationship study, the parent compound
1 from high-throughput screening was still the best among
other small molecules that we prepared. Previously reported
Figure 2. (a) High-throughput screening (HTS) of chemical compounds
from Korea Chemical Bank. (b) Structure and biochemical activity of
compound 1 from HTS.
High-throughput screening (HTS) was performed to search of
a potent SHP2 inhibitor. First we screened 10,409 compounds

allosteric inhibitors such as SHP099 and SHP244 have
nitrogen containing heteroaromatic rings with an amine or an
alcohol in their structures and these make them possible for
hydrogen bonds. Interestingly, compound 1 does not have any
nitrogen atoms in the structure. Instead oxygen-containing
functional groups including three hydroxy groups, one ketone,
and one carboxylic acid participate in hydrogen bonding
interactions.

O
OH
OH
R2
HO
R1
1, 2a-2n
compound R1
R2
entry
compound
R1
R2
Inhibition SHP2 IC50
Inhibition SHP2 IC50
entry
(%)
(μM)
(%)
(μM)
1
2
3
4
5
6
7
1
H
H
H
H
H
H
H
CO2H
CO2Me
CO2Et
93
0.097
9
2h
2i
OMe
CONH2
CO2Me
CO2H
0
ND
2a
2b
2c
2d
2e
2f
87
50
2
0.161
0.985
4.870
4.110
1.230
ND
10
11
12
13
14
15
OMe
6
90
8.658
0.277
7.552
6.544
0.949
7.743
2j
F
F
F
F
F
i
CO2 Pr
2k
2l
CO2Me
CO2Et
12
CONH2
CN
13
40
0
19
2m
2n
CONH2
52
i
H
CO2 Pr
0.47
O
N
8
2g
H
29
1.573
Cl
ND = not determined
Table 1. Structure activity relationship study of SHP2 inhibition activities
Three compounds with high potencies against SHP2, 1, 2a,
and 2j, were selected for further biological activity study, and
a reported allosteric inhibitor, SHP099, was purchased and
used as a reference compound for comparisons. MDA-MB-468
viability after treating SHP2 inhibitors were determined
(Figure 3a), and IC50 of 5.3, 4.6, and 71 μM were obtained,
respectively. The data suggest that potency against SHP2
correlates with viability of SHP2 expressed cancer cells.
Compounds 1 and 2a exhibited 5.6 and 4.2 fold lower IC50
values compared to SHP099 (29.9 μM of IC50) and these
results suggested 1 and 2a were superior SHP2 expressed
cancer cell killing ability. Knockdown of SHP2 with SHP2
siRNA greatly decreases proliferation inhibition of compounds, 1,
2a, and 2j, showing 19.3, 3.0 and 16.3 fold increased in MDA-
MB-468 viability in the presence of each compound with 100 μM
respectively (Figure 3b, 3c and 3d). This result suggested that 1,
2a and 2j exerted potency against cancer cells through inhibition
expressing 3D cancer spheroid than SHSP099. Taken together,
these data suggest that compounds 1 and 2j showed stronger
potency than known SHP2 inhibitor SHP099 in SHP2 expressing
of SHP2.
O
OH
OH
HO
OR
O
2D and 3D cancer cells.
3
Figure 3. MDA-MB-468 viability (a) in the presence of SHP2 inhibitors
(b) with control and SHP2 siRNA with compound 1 (c) compound 2a (d)
compound 2j.
entry
compound
R
Inhibition (%) SHP2 IC50 (μM)
1
2
3a
3b
H
0
0
ND
ND
Me
Figure 4. MDA-MB-468 3D spheroid viability in the presence of SHP2
ND = not determined
inhibitors.
Table 2. Structure activity relationship study of SHP2 inhibition activities.
We conducted enzyme kinetic study of compound 1 and data
is suggesting that compound 1 may noncompetitively inhibit
SHP2 (Supplementary Figure 1), therefore the binding
mechanism of compound 1 was further studied via molecular
To test SHP2 inhibitors on 3D culture, MDA-MB-468
spheroids were fabricated. 20 μM of 1, 2a, and 2j, showed 35.7,
27.5 and 37.2% decrease in 3D MDA-MB-468 viability (Figure
4). IC50 values for SHP2 inhibitor SHP099, 1, 2a and 2j were
49.6, 35.8, 62.9 and 39.2 μM respectively. Although exerting
decreased anticancer potency (on average 43.7%), compounds 1
and 2j still showed higher anticancer potency against SHP2

modeling. Glide 8.3 software implemented in Maestro 12.0 was
used for docking studies.29 The crystal structure of SHP2 (PDB
code : 5EHR) obtained from the Protein Data Bank was used as
the receptor with structural defects fixed by the Protein
Preparation Wizard module.
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Figure 5. Predicted binding pose of compound 1 (purple sticks) in the
allosteric binding site of SHP2. SHP2 is drawn by ribbons along with the
interacting residues represented as sticks, and hydrogen-bonding interactions
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of SHP2 (Figure 5). The activity of 1 was mainly attributed to
several strong hydrogen bond interactions and hydrophobic
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with Arg111 and nitrogen of Thr218 and Thr219. This hydrogen
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In conclusion, compound 1 with IC50 of 0.097 μM was
obtained from high-throughput screening using chemical libraries
from Korea Chemical Bank. Efforts by structure-activity
relationship to improve SHP2 inhibition activities was not
superior to this parent compound. Compound 1 exerted higher
potency against SHP2 expressing 2D and 3D MDA-MB468 than
SHP099. Further study is underway and will be reported in due
course.
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Acknowledgments
The authors thank to Korea Chemical Bank to offer chemical
libraries for HTS study, and acknowledge the financial support
from
National
Research
Foundation
of
Korea
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Fodor, M.; Gao, H.; Ho, S.; Hsiao, K.; Kang, Z.; Keen, N.;
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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