Identification and synthesis of N-(thiophen-2-yl) benzamide derivatives as BRAFV600E inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.02.072

The V600E BRAF kinase mutation, which activates the downstream MAPK signaling pathway, commonly occurs in about 8% of all human malignancies and about 50% of all melanomas. In this study, we employed virtual screening and chemical synthesis to identify a

Full text of DOI:10.1016/j.bmcl.2013.02.072

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2306–2312
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification and synthesis of N-(thiophen-2-yl) benzamide
derivatives as BRAFV600E inhibitors
d
Yunfeng Xie a, , Xianjie Chen b, , Jie Qin c, , Xiangqian Kong d, Fei Ye d, Yuren Jiang a, , Hong Liu ,
⇑
Hualiang Jiang b,d, , Ronen Marmorstein c, Cheng Luo d,
⇑
⇑
a College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, China
b School of Chemistry and Chemical Engineering, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, China
c The Wistar Institute, Philadelphia, PA 19104, USA
d State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The V600E BRAF kinase mutation, which activates the downstream MAPK signaling pathway, commonly
occurs in about 8% of all human malignancies and about 50% of all melanomas. In this study, we
employed virtual screening and chemical synthesis to identify a series of N-(thiophen-2-yl) benzamide
derivatives as potent BRAFV600E inhibitors. Structure–activity relationship studies of these derivatives
revealed that compounds b40 and b47 are the two most potent BRAFV600E inhibitors in this series.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 1 January 2013
Revised 4 February 2013
Accepted 14 February 2013
Available online 26 February 2013
Keywords:
BRAF
Kinase inhibitors
Virtual screening
Anticancer agents
Ras/RAF/MEK/ERK signal transduction cascades play critical
roles in transducing signals from extracellular growth factors to
the nucleus and participate in many cellular programs, such as cell
proliferation, differentiation, and survival.1–3 These cascades are
intimately involved in many human cancers mainly because a large
number of oncogenic mutations have been frequently identified in
rapidly growing fibrosarcoma (RAF) family members,4 including
ARAF, BRAF, and CRAF.5 RAF protein kinases play central roles in
the MAPK signaling pathway and have been shown to be critical
in mediating cell proliferation, differentiation, and survival.6,7
Among the three paralogs of RAF, oncogenic mutations in BRAF
are the most frequently observed in human cancers.4 The BRAF
gene is located on human chromosome 7q24 and encodes a cyto-
solic serine–threonine protein kinase that is expressed in many hu-
man cell types.8 The BRAF oncogene is mutated in approximately
8% of all human tumors, and especially in melanoma (ꢀ50%), pap-
illary thyroid (ꢀ50%), ovarian (ꢀ25%), and colorectal (ꢀ12%) can-
cer.6–8 The most common BRAF mutation is the replacement of
valine with glutamic acid at position 600 (V600E), which accounts
for over 90% of all BRAF mutations in cancers and aberrantly drives
the activation of the MAPK signaling pathway, thus facilitating
malignant transformation.7,9–12 Thus, BRAFV600E has emerged as a
promising therapeutic cancer target.5,13,14
To date, various inhibitors of BRAF have been evaluated in clin-
ical trials, such as CEP-32496, LGX-818, ARQ-736, and RG-7256 in
phase I clinical trials. DCC-2036 has been tested in phase II clinical
trials, dabrafenib has been tested in phase III clinical trials, rego-
rafenib is in pre-registration, and vemurafenib has been made pub-
licly available.15 However, recent data indicate that patients
eventually develop significant drug resistance to these inhibi-
tors16,17 or suffer severe side effects.18 Therefore, the development
of novel, potent BRAFV600E inhibitors that may that may not suffer
from these limitations is of significant importance.
High-throughput screening and structure based virtual screen-
ing (SBVS) are two screening methods frequently used by medici-
nal chemists. Indeed, most of the currently available BRAF kinase
inhibitors have been identified by these two complementary ap-
proaches.19–21 In our previous work, a series of 2-phenyl-5-vinylfu-
ran derivatives were identified as potent novel BRAFV600E inhibitors
based on SBVS and chemical optimization.22 In the present study,
N-(thiophen-2-yl) benzamide derivatives are reported as another
series of BRAFV600E selective inhibitors. In particular, compounds
b40 and b47 in this series exhibit submicromolar inhibitory activ-
ities against the BRAFV600E kinase.
⇑
Corresponding authors. Tel.: +86 731 88879616; fax: +86 731 88859988 (Y.J.);
Molecular docking methods and SBVS are commonly used ap-
proaches in hit identification.23 To find more potent compounds
with novel scaffolds toward BRAFV600E, a hierarchical virtual
tel.: +86 21 50806600; fax: +86 21 50807088 (H.J. and C.L.).
E-mail addresses: jiangyr@mail.csu.edu.cn (Y. Jiang), hljiang@mail.shcnc.ac.cn
(H. Jiang), cluo@mail.shcnc.ac.cn (C. Luo).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.072

Y. Xie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2306–2312
2307
Table 1
BRAFV600E inhibition activity data for compounds a1–a22
R2
O
O
O
S
R1
N
H
R3
Compound
R1
R2
R3
Inhibition (%) (at 2
l
M)
IC50 (lM)
a22f22
0.47
a1
a2
–CH2CH3
–CH2CH3
CN
CN
52
42
2.01
ND
O
Cl
a3
a4
–CH2CH3
–CH2CH3
CN
CN
NA
36
ND
ND
NO2
a5
a6
a7
–CH2CH3
–CH2CH3
–CH2CH3
CN
CN
CN
46
69
NA
ND
O
1.16
ND
Br
NO2
a8
–CH2CH3
–CH2CH3
–CH2CH3
CN
CN
CN
51
32
NA
2.16
ND
Cl
O
O
a9
O
a10
ND
O
a11
a12
–CH3
–CH3
CN
CN
NA
NA
ND
ND
O
O
a13
–CH3
CN
NA
ND
a14
a15
O
F
–CH(CH3)2
–CH(CH3)2
CN
CN
NA
NA
ND
ND
Cl
a16
–CH(CH3)2
CN
42
ND
Cl
O
I
a17
a18
–CH2CH3
–CH2CH3
CN
NA
NA
ND
ND
–COOCH2CH3
a19
–CH2CH3
–COOCH3
NA
ND
(continued on next page)

2308
Y. Xie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2306–2312
Table 1 (continued)
Compound
R1
R2
R3
Inhibition (%) (at 2
NA
lM)
IC50
ND
(lM)
F
F
a20
–CH2CH3
–COOCH2CH2CH3
a21
a22
–CH2CH3
–CH2CH3
–CONH2
–CONH2
NA
26
ND
ND
Cl
NA = not active; ND = not determined.
a
Compound 22f from Ref. 22 was assayed as control.
screening process was initiated. First, the SPECS database, which
contains more than 200,000 chemicals (http://www.specs.net),
was filtered using drug-like criteria24 to create a focused library
containing about 50,000 theoretically drug-like small molecules.
Next, the compounds were docked into the ATP-binding site of
the BRAFV600E kinase (PDB entry: 3OG725) using the GLIDE26 pro-
gram in standard precision mode. The top 2000 compounds were
submitted for further evaluation using the GLIDE extra precision
mode. The top 500 compounds were then retained for structural
diversity analysis. Finally, 30 compounds from 38 manually classi-
fied groups were purchased and evaluated for their ability to inhi-
bit the enzymatic activity of BRAFV600E. An ELISA-based MEK
phosphorylation assay, which was performed according to our pre-
vious work,22 revealed that the N-(thiophen-2-yl) benzamide
derivative, a1, was the most potent BRAFV600E kinase inhibitor with
substitution of an ethyl group. However, a17, containing a furan-
2-carboxamide showed a loss of inhibitory enzyme potency, high-
lighting the superior performance of a substituted phenyl group at
R1. In addition, comparison of the activities of a8, a16, a4 and a22
revealed that double substitution at the ortho- and para-positions
of the phenyl group was desirable. Moreover, substitution of the
cyano group at R3 with an ester or amide group exhibited substan-
tially reduced activity (e.g., compounds a18–a21). Compound a22,
which features a 4-chloro phenyl group at R1 and an amide substi-
tution at R3, retained some inhibitory activity against BRAFV600E
.
To better understand the molecular mechanism of BRAFV600E
inhibition by these compounds, the most potent inhibitor (a6)
was docked to the active site of BRAFV600E 22
The docking results
.
suggest that a hydrophobic interaction may occur between the eth-
oxy group of the phenyl ring of a6 and the hydrophobic pocket
an IC50 value of about 2.01
lM (Table 1). Since few studies demon-
formed by S535, F583, and C532 of BRAFV600E (Fig. 1). A
p–p stack-
strated that N-(thiophen-2-yl) benzamide derivatives were poten-
tial BRAFV600E kinase inhibitors,4,27–30 a1 was chosen for further
studies.
To explore the structure–activity relationship (SAR) of a1, a
similarity-based analogue search was performed in the SPECS
database, and another 21 compounds were selected based on the
search results from the vendor database and their inhibitory activ-
ities against BRAFV600E were assessed. As shown in Table 1, the
BRAFV600E inhibitory activities of a2 and a6 were better than a11
and a14, indicating that better inhibition could be obtained by R2
ing interaction is also predicted to occur between the phenyl ring
of a6 and F583 of BRAFV600E. This modeling also predicts a hydro-
phobic interaction between the inhibitor thiophen ring and L514
of BRAFV600E, a hydrogen bond formed by the oxygen atom of the
amide between the phenyl and thiophen rings of a6 with the hy-
droxyl of T529 of BRAFV600E, and the inhibitor ester group of the
thiophen ring extended toward the activation loop, yielding favor-
able interactions with D594, I527, and L505 of BRAFV600E. Another
hydrogen bond is predicted to form between the nitrogen atom of
K483 of BRAFV600E and the oxygen atom of the ester group of the
Figure 1. Docking results of compound a6 with BRAFV600E kinases. Left panel: BRAFV600E kinase in the active conformation (PDBID: 3OG7). The a6 molecules that occupy ATP
bonding sites are shown as sticks in yellow. Right panel: the close-up view of the key interactions between compound 6 and 3OG7 Hydrogen bonds are shown as dotted blue
lines.

Y. Xie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2306–2312
2309
Table 2
BRAFV600E inhibition activity data for compounds b23–b47
O
O
O
S
R1
N
H
R3
Compound
R1
R3
Inhibition (%)
IC50
ND
(lM)
2
l
M
1 lM
F
b23
–CN
51
ND
Cl
b24
b25
b26
–CN
–CN
–CN
57
50
13
ND
ND
ND
ND
ND
ND
O
CN
b27
–CN
40
ND
ND
b28
b29
O
–CN
–CN
15
54
ND
ND
ND
ND
O
O
b30
b31
b32
–CN
–CN
–CN
48
60
NA
ND
ND
ND
ND
ND
ND
Cl
N
N
H
N
b33
b34
b35
–CN
–CN
–CN
ND
ND
ND
17
ND
ND
ND
O
O
NA
NA
NH
H
N
O
S
O
H
N
O
S
b36
b37
b38
–CN
–CN
–CN
ND
ND
59
NA
NA
ND
ND
ND
ND
O
H
N
O
S
O
F
F
Cl
Cl
b39
b40
–CN
–CN
36
85
ND
60
ND
O
O
0.77
(continued on next page)

2310
Y. Xie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2306–2312
Table 2 (continued)
Compound
R1
R3
Inhibition (%)
IC50
ND
(lM)
2
l
M
1 lM
b41
–CN
60
ND
Cl
F
H
N
O
S
b42
b43
–CN
–CN
ND
ND
34
39
ND
ND
O
F
N
N
b44
b45
b46
b47
–CN
ND
ND
ND
87
20
22
10
66
ND
ND
ND
0.63
N
–CN
N
–CN
Cl
F
–CONHC6H6
NA = not active; ND = not determined.
inhibitor. Moreover, the cyano group of the inhibitor is predicted to
occupy a small hydrophobic pocket created by A481, V471, and
the phenyl ring was substituted by ethoxyl or chlorine. However,
when chlorine was substituted by bromine, inhibition potency
was lost. In these compounds, the difference in influence between
EWG and EDG was not obvious. Inhibitory activity was entirely lost
when a piperazine ring was introduced at the para-position of the
phenyl ring (b32). Compounds b33–b37, b42, and b46 were de-
signed to possess the potential to form hydrogen bonds. However,
consistent with our docking results, no significant improvement
in inhibition potency was achieved by these compounds, indicating
that the phenyl group may point into solvent (Fig. 2). Based on the
aforementioned SAR data, double substitution of the phenyl group
may improve inhibitory activity. Thus, compounds b38–b41, which
possess diverse double substitutes, were synthesized. Compound
K483 of BRAFV600E
.
Based on the docking result of a6 with BRAFV600E, another set of
25 a1 analogs were synthesized using the condensation reaction
(see Supplementary data); the bioactivity data of these analogs
are listed in Table 2. Comparable activity between a2 and b23 indi-
cates that both electron-donating groups (EDG) and electron-with-
drawing groups (EWG) are well tolerated at the ortho-position of
the phenyl ring. Compounds a4 and b24–b27 showed that substitu-
tion of a hydrogen atom by a chlorine atom at the meta-position
correlates with better inhibition activity. In addition, when the phe-
nyl group in the meta-position was substituted by chlorine (b24),
the resulting compound showed more potency compared with
compounds with replacements using other elements (e.g., a4,
b25–b27.) The activity data of a5, a6, and b28–b31 indicate that
the inhibitory activities were improved when the para-position of
b40 had an IC50 value of about 0.77 lM. From the docking result
in Figure 1, a small vacuity of the pocket around the cyano group
was proposed. To further verify this hypothesis, b47 was designed
and synthesized. Interestingly, b47 possessed the most potent
Figure 2. Docking results of compound b47 with BRAFV600E kinase. Compound b47 and salt bridges are shown in blue.

Y. Xie et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2306–2312
2311
Figure 3. Kinase inhibition profiles of compounds b40 and b47 against a panel of 16 protein kinases compared with BRAFV600E
.
inhibitory activity against BRAFV600E with an IC50 value of 0.63
lM.
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Upon close inspection of the putative binding mode of b47, a dis-
tinct binding mode within the active site of BRAFV600E was pre-
dicted (Fig. 2), wherein an inverted orientation was observed to
remarkably strengthen the geometric and chemical features of
b47 with the receptor, to better accommodate BRAFV600E. This find-
ing suggests that b47 may represent a novel chemotype with
acceptable biological potency for oncogenic BRAFV600E inhibition.
To exploit the selectivity profile of this novel chemotype, the
specificity and selectivity of the two most potent inhibitors against
BRAF (b40 and b47) were cross-screened over a small panel of 16
other kinases. The results shown in Figure 3 reveal significant lev-
els of BRAFV600E inhibitor selectivity against this small pool of tyro-
sine- and serine/threonine-kinases.
In summary, a series of N-(thiophen-2-yl) benzamide deriva-
tives have been developed as novel BRAFV600E kinase inhibitors uti-
lizing SBSV and chemical optimization. Two of these compounds
(b40 and b47) exhibited submicromolar inhibitory activities, with
the potential for future development as BRAFV600E—selective ki-
nase inhibitors for cell-based and clinical studies.
Acknowledgments
We gratefully acknowledg the financial support from the Na-
tional Natural Science Foundation of China (20972174, 91029704,
21210003 and 21021063), the State Key Program of Basic Research
of China Grant (2009CB918502), 863 program (2012AA020302),
the National Science and Technology Major Project ‘Key New Drug
Creation and Manufacturing Program’ (2013ZX09507-004), and
the National Institutes of Health (CA114046).
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Supplementary data
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