Synthesis and Biological Evaluation of 3-Arylindazoles as Selective MEK4 Inhibitors

Article abstract of DOI:10.1002/cmdc.201900019

Herein we report the discovery of a novel series of highly potent and selective mitogen-activated protein kinase kinase 4 (MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signaling pathways that phosphorylates p38 MAPK and JNK in response to mitogenic and cellular stress queues. MEK4 is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. Optimization of this series via structure–activity relationships and molecular modeling led to the identification of compound 6 ff (4-(6-fluoro-2H-indazol-3-yl)benzoic acid), a highly potent and selective MEK4 inhibitor. This series of inhibitors is the first of its kind in both activity and selectivity and will be useful in further defining the role of MEK4 in prostate and other cancers.

Full text of DOI:10.1002/cmdc.201900019

Accepted Article
Title: Synthesis and Biological Evaluation of 3-Arylindazoles as
Selective MEK4 Inhibitors
Authors: Karl Scheidt, Kristine K. Deibler, Gary E. Schiltz, Matthew
R. Clutter, Rama K. Mishra, Purav P. Vagadia, Matthew
O’Connor, Mariam Donny George, Ryan Gordon, Graham
Fowler, and Raymond Bergan
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.201900019
Link to VoR: http://dx.doi.org/10.1002/cmdc.201900019
A Journal of
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10.1002/cmdc.201900019
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COMMUNICATION
Synthesis and Biological Evaluation of 3-Arylindazoles as
Selective MEK4 Inhibitors
Kristine K. Deibler,[a] Gary E. Schiltz,[b,c,d] Matthew R. Clutter,[d,e,f] Rama K. Mishra,[b,c] Purav P.
Vagadia,[b] Matthew O’Connor,[a] Mariam Donny George,[e] Ryan Gordon,[g] Graham Fowler,[g] Raymond
Bergan,[g] and Karl A. Scheidt*[a,b,c,d,e]
[a]
K. Deibler, Dr. M. O’Connor, Prof. K.A. Scheidt
Department of Chemistry, Northwestern University, Evanston, 60208, Illinois, USA
E-mail: scheidt@northwestern.edu
[b]
Dr. G.E. Schiltz, Dr. R.K. Mishra, P.P. Vagadia, Prof. K.A. Scheidt
Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, Illinois, 60208, USA
Dr. G.E. Schiltz, Dr. R.K. Mishra, Prof. K.A. Scheidt
Department of Pharmacology, Northwestern University, Chicago, 60611, Illinois, USA
Dr. G.E. Schiltz, Dr. M.R. Clutter, Prof. K.A. Scheidt
Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA
Dr. M.R Clutter, M.D. George, Prof. K.A. Scheidt
Chemistry of Life Process Institute, Northwestern University, Evanston, 60208, Illinois, USA
Dr. M.R. Clutter
[c]
[d]
[e]
[f]
Department of Molecular Biosciences, Northwestern University, Evanston, 60208, Illinois, USA
Dr. R. Gordon, G. Fowler, Dr. R. Bergan
[g]
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein we report the discovery of a novel series of highly
potent and selective mitogen-activated protein kinase kinase 4
(MEK4) inhibitors. MEK4 is an upstream kinase in MAPK signalling
pathways that phosphorylates p38 MAPK and JNK in response to
mitogenic and cellular stress queues. MEK4 is overexpressed and
induces metastasis in advanced prostate cancer lesions. However,
the value of MEK4 as an oncology target has not been
pharmacologically validated because selective chemical probes
targeting MEK4 have not been developed. Optimization of this series
via structure activity relationships and molecular modelling led to the
identification of compound 6ff (4-(6-fluoro-2H-indazol-3-yl)benzoic
acid), a highly potent and selective MEK4 inhibitor. This series of
inhibitors is the first of its kind in both activity and selectivity and will
be useful in further defining the role of MEK4 in prostate and other
cancers.
MEK4 are potential drug targets in combination with current MEK
inhibitors, in spite of the fact that they are encoded by putative
tumor suppressor genes.
O
Cl
N
OH
OH
O
O
O
OMe
OMe
HO
R = t-BuMe2SiO
R
1 (HWY336)
2 (THIF)
Figure 1. Structures of previously reported MEK4 inhibitors.
MAPK signaling cascades are dysregulated in human cancer
and inflammatory diseases, and small molecule inhibitors
targeting MAPK signaling components are under intense
investigation in the clinic.[1] A majority of MEK inhibitors target
MEK1/2 including the FDA approved drug trametinib/Mekinist.[2]
Most clinically relevant MEK inhibitors today target the MEK1/2
allosteric site and therefore show no activity against MEK3/4/5/6
or 7. As a result, there is a dearth of chemical matter directed at
these other MAPK kinase family members, which is surprising
given their roles in a host of biological processes. Consequently,
their value as therapeutic targets has not been thoroughly
investigated and new compounds that are selective for MEK
family kinases beyond MEK1/2 could have tremendous potential.
Most clinical studies with MEK inhibitors have yielded
disappointing results, due at least in part to the paucity of
biomarkers of MEK inhibitor sensitivity and toxicity. Bernards and
co-workers recently showed data suggesting that cancers having
mutations in MEK4 or its upstream kinase MEKK1, which are
frequent in tumors of breast, prostate and colon, may respond to
MEK inhibitors.[3] Their findings also suggest that MEKK1 and
MEK4 (also known as MAP2K4, MKK4, SEK1) is a dual-
specificity kinase, i.e., it phosphorylates serine/threonine as well
as tyrosine residues, and it constitutes a second tier signaling
protein of the canonical three-tier MAPK cascade.[4] MEK4 has
become a target of interest for the therapeutic inhibition of
prostate cancer (PCa) metastasis.[5] Although often described
only as an activator of JNK, MEK4 also activates p38α and p38β,
which complicates any investigation in this area.[1d] MEK4 is
overexpressed in advanced PCa lesions and induces invasion
and metastasis in PCa.[5-6] MEK4 also appears to have a similar
pro-invasion/pro-metastatic role in several other cancer types,
including breast and pancreatic cancers.[7] Through genetic and
chemical approaches, MEK4 was shown to increase the invasive
potential of PCa cells in vitro by upregulating the production of
several matrix metalloproteinases (MMP’s) in response to TGF-β
treatment.[5, 6d] Overexpressing MEK4 increased the number of
metastatic deposits observed in a PCa mouse model.[6d] These
1
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10.1002/cmdc.201900019
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findings present MEK4 as a clinically important therapeutic target
and underscore the need to develop selective MEK4 probes for in
vivo target validation in advanced cancer model systems.
To date, in the literature there has been minimal advancement
in MEK4 inhibitor development. HWY336 (1), a protoberberine
derivative, inhibits both MEK4 and MEK7 (Figure 1).[8] HWY336
not only has poor selectivity and only moderate potency, but the
pharmacological parameters are not ideal as it is a tetracyclic
alkaloid, a compounds class known for promiscuity in biological
effects.[9] Trihydroxyisoflavones have also been shown to have
effects against MEK4 but not in a selective manner.[10] These
isoflavones again are rather non-selective, for example 7, 3’, 4’-
trihydroxyisoflavone (THIF, 2) also inhibits Cot activity.[10a] The
current landscape of chemical tools to probe this important kinase
further stresses the need to develop selective and
pharmacologically robust MEK4 inhibitors.
Recognizing that MEK4 represents a novel and validated
therapeutic target we sought to identify and characterize selective
MEK4 inhibitors. Previously, we developed a platform for mapping
the pharmacological relatedness of all seven MEK kinase family
members to understand compound selectively.[11] Herein we
discuss leveraging that foundational platform to screen
compounds and identify a potent and selective hit molecule.
Optimization and biological evaluation gave further insight into
potential utilization of this series of compounds as selective MEK4
inhibitors.
To discover new inhibitors of MEK4, a library of 50,000 diverse
compounds (commercially available ChemBridge DIVERSet-CL)
was screened using an enzymatic ADP-Glo assay with active
recombinant human MEK4 and full-length p38a substrate. The
library was calculated to have a diversity index of 0.73 and
determined that >90% of the compounds adhered to drug-like
filters including Lipinski, Veber, and Pipeline Pilot SMARTS filters.
Several compounds exhibited potent activity, and for this study
subsequent work focused on a relatively small hit compound with
an indazole core that inhibited MEK4 by 92% at 10 µM in the initial
screen (Figure 2A, 6a). LC/MS analysis of the compound
confirmed its mass and that its purity was > 95% (data not shown).
Compound 6a was next tested to determine if its activity could
be attributed to compound aggregation. A large fraction of hit
compounds in wide-ranging HTS campaigns have been found to
inhibit the target protein by forming hydrophobic aggregates that
nonspecifically interact with the protein.[12] Since detergents have
been shown to disrupt compound aggregation, a common way to
identify these artifacts is by adding detergent to the assay and
looking for a substantial or complete loss of potency. Inhibitor 6a
was tested at several concentrations in the ADP-Glo assay using
a buffer with and without 0.01% Triton X-100, and similar MEK4
inhibition profiles were observed in both cases (Figure 2B).
Additionally, 6a was examined by dynamic light scattering (DLS),
another common way to identify compound aggregates. The
compound was tested at 20, 5, and 1 µM in buffer with and without
Triton X-100, and under no conditions were aggregates observed
(data not shown).
tagged tracer bound to the MEK4 active site. Inhibitor 6a at 10 µM
reduced the TR-FRET ratio to background levels, similar to 10 µM
Figure 2. Identification and validation of 6a. (A) High throughput chemical
screen using a functional ADP-Glo assay revealed 6a as one of the most active
hit compounds against MEK4. (B) 6a was tested with and without detergent in
the ADP-Glo assay at three doses (n=2-4). (C) TR-FRET was used to evaluate
competitive binding with an active site tracer to MEK4 (n=6). (D) 6a was tested
at four different ATP concentrations and potency was determined using a
logistic regression curve fit (n=2). (E) Thermal stability of various MEK4
constructs was analyzed with vehicle (grey curves) or 6a (blue curves) using a
Boltzmann curve fit. Data is representative of two independent runs. (F) 6a was
titrated against the seven MEK family proteins to calculate the potency in each
system by logistic regression (n=2).
staurosporine, a low nanomolar MEK4 and pan-kinase tool
inhibitor (Figure 2C).
The ability of 6a to displace the active site TR-FRET probe,
along with the potential for kinase hinge binding by the indazole
moiety, suggested that the compound likely binds to the ATP
pocket of the MEK4 active site. To further characterize the binding
mode, an ATP titration experiment was performed. Direct ATP-
competitive inhibitors generally experience a loss of potency
when tested in the presence of high ATP concentrations,
particularly at concentrations above the enzyme’s KM for ATP.[13]
To ensure 6a does not nonspecifically interfere with the ADP-
Glo assay technology (for example, as a luciferase inhibitor) 1µM
ADP was spiked in to simulate enzymatic ATP turnover and no
reduction in the luminescent signal at 20, 10, and 5 µM of
compound was observed (data not shown). To further validate 6a
as a bona fide MEK4 inhibitor, an orthogonal TR-FRET assay was
used to determine if the compound could displace a fluorescently-
2
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We determined the KM of MEK4 for ATP to be 3.0 ± 0.4 µM, so 6a
was tested at eight doses each with 1, 4, 12, and 45 µM of ATP.
The potency of the inhibitor decreased with each stepwise
increase in ATP concentration, suggesting an ATP-competitive
binding mode (Figure 2D). As expected, a smaller shift was
observed from 1 to 4 µM since 4 µM approximates the KM value.
Next, the fluorescence thermal shift (FTS) assay was used to
determine the change in thermal stability of MEK4 in the presence
of 6a. The stability of a protein is commonly altered when it binds
a ligand, and we previously demonstrated that a hallmark of
MEK4 inhibitors is increased thermal stability.[14] Compound 6a
increased the melting temperature of three MEK4 constructs: (1)
phosphorylated (active) full-length MEK4 (the same construct
used in the ADP-Glo and TR-FRET assays described above), (2)
the nonphosphorylated (inactive) kinase domain of MEK4, and (3)
a
mutant (S257E/T261E) phosphomimetic (partially active)
version of the kinase domain, each by 5-6 degrees (Figure 2E).
This suggests 6a has little preference for binding the active versus
inactive forms of MEK4.
Figure 3. Modelling of 6a. Docked pose of 6a with MAP2K4. Key interactions
are highlighted, including those with hinge residues Leu180 and Met181, as well
as an electrostatic interaction between the carboxylate and Lys187.
Finally, to investigate if 6a exhibits specificity for MEK4 relative
to the other six MEK isoforms (which have 38-61% homology to
MEK4), an ADP-Glo MEK assay panel[11] was used to determine
the potency of this inhibitor against all seven MEK enzymes. The
assays were run at a saturating concentration of full-length protein
substrates (Erk2, Erk5, p38a, or Jnk1ß), and an ATP
concentration below the KM of ATP for each enzyme. The potency
of 6a against MEK4 was 0.19 µM and 0.38 µM using p38a and
Jnk1ß substrates, respectively. In comparison, the next most
potent target was MEK1, with an IC50 of 12 µM, indicating that 6a
has 30- to 60-fold selectivity for MEK4 relative to any other MEK
protein (Figure 2F).
The identification and validation of 6a as a novel ATP-
competitive MEK4 inhibitor prompted us to model its binding to
MEK4 and subsequently carry out medicinal chemistry in an effort
to further improve its potency and selectivity. Molecular modeling
of compound 6a bound to MEK4 was carried out using the Glide
docking engine implemented in the Schrӧdinger suite.[15] Several
key interactions were identified from the molecular modeling.
When analyzing the predicted binding poses of 6a, critical
hydrogen bonding interactions in the hinge region between the
small molecule and the backbone of MEK4 residues Leu180 and
Met181 were observed (Figure 3). The predicted binding poses
are consistent with it being an ATP-competitive inhibitor (Figure
2D). Modeling also indicated a favorable electrostatic interaction
between the 6a carboxylate and Lys187. In addition, there
appeared to be space extending from the 5- and 6- position of the
indazole ring that was unoccupied. Replacement of the
carboxylate with other hydrogen bond acceptors could maintain
or strengthen this interaction while modulating the physiochemical
properties of the inhibitors.
deprotection was carried out separately using TFA. For final
compounds containing carboxylic acids, their methyl ester boronic
acid was used in the Suzuki reaction and subsequent hydrolysis
was then performed to generate the carboxylic acid.
Based on molecular modeling of unsubstituted indazole 6a, it
was expected that introduction of small hydrophobic groups on
the indazole ring could occupy a back hydrophobic pocket.
Addition of methyl- or chloro- groups at the indazole 4-position
resulted in compounds with significantly decreased potency
(Table 1). In contrast to unfavorable substitutions on the 4-
position, addition of several different small hydrophobic groups on
the 5-position resulted in compounds with greater MEK4 potency.
Addition of a 5-CF3 group onto the indazole in combination with
4’-CO2H (6n) or 4’-OH (6j) resulted in inhibitors with comparable
potency to the original unsubstituted hit compound (6a). The
inhibitor with a CH3 on the 5-position and a 4’-OH on the 3-aryl
ring (6q) was almost 7-times more potent than the analogous 4-
CH3-substituted indazole compound (6b). Compounds with a 5-
CH3 on the indazole tended to be more potent when the 3-aryl
ring was substituted at the 4’-position. Compounds with a Boc-
group on the indazole N-1 were completely inactive, which is
consistent with the modeling which shows the indazole N-H
forming a key interaction with the kinase hinge region. While
exploring the activity of 6-CF3 analogs, the importance of the 3-
aryl carboxylic acid moiety was also examined. Inhibitors with a
methyl ester instead of an acid (e.g. 6y) were completely inactive,
while their carboxylic acid analog (6z) showed potent inhibition
(IC50 of 0.72 µM). It was found that chloro-substituted indazoles
possessed improved potency compared with their -CH3 or -CF3
analogs. Finally, several indazoles with a fluorine on the indazole
6-position were prepared and showed excellent potency for MEK4
(6ee and 6ff) and were 5- and 10-fold more potent (respectively)
than their 6-Cl analogs. Based on further molecular docking
studies (Figure S1) it is suspected that the fluorine stabilizes most
favourable planar confirmation of the compound while being the
optimal size for the small polar/solvent expose region.
Synthesis of the new indazole analogs proceeded as shown in
Table
1 starting with commercially available indazoles 1.
Selective iodination at the 3-position was achieved using NaOH
and iodine to provide the intermediate in yields ranging from 90-
95% yield. The iodinated heterocycle was then treated with Boc2O
to protect the free N-H group, since it was found that unprotected
indazoles either failed in the subsequent Suzuki reaction or had
dramatically slower reaction rates. Thus, treatment of iodides 2
with a range of boronic acids (3) provided the final 3-aryl indazoles
4 in moderate to good yields. In several cases, the Boc-protecting
group was lost during the course of the Suzuki reaction. In others,
Having improved the MEK4 potency of our lead series, several
of the most potent inhibitors were profiled against the entire MEK
family to evaluate selectivity (Table 2). It was found that all
compounds tested inhibited MEK4 more potently than any other
3
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10.1002/cmdc.201900019
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COMMUNICATION
Table 1. Synthesis and SAR of substituted 3-aryl indazoles.
4’
3’
5’
R2
2’
I
6’
a
b
R1
R1
N
N
N
R1
N
H
N
H
N
R2
Boc
HO
B
OH
3
4
6a-ff
5
MEK4-p38, IC50, µM
[95% CI]
MEK4-p38, IC50, µM
[95% CI]
Compound
R1
R2
Compound
R1
R2
6a
6bb
6c
6d
6e
6f
H
3’-CO2H
4’-OH
0.64 [0.53, 0.77]
4.0 [3.3, 4.8]
4.5 [3.9, 5.2]
4.4 [3.9, 5.0]
> 22
6q
6r
5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
5-CH3
6-CF3
6-CF3
6-CF3
6-Cl
4’-OH
0.59 [0.46, 0.75]
0.56 [0.40, 0.77]
0.15 [0.10, 0.23]
1.6 [1.1, 2.3]
4-CH3
4-Cl
4’-CONH2
4’-CO2H
3’,4’-(OCH2O)
4’-CONH2
3’-pyridyl
3’-CH2OH
3’-C(CH3)OH
3’-CONH2
4’-CH2OH
4’-OH
6s
4-Cl
6t
3’-pyridyl
3’-CH2OH
3’-CONH2
4’-CH2OH
4-Cl
6u
1.4 [1.2, 1.8]
4-Cl
7.2 [6.0, 8.6]
> 22
6v
0.97 [0.74, 1.3]
1.3 [1.1, 1.5]
6g
6h
6i
4-Cl
6w
6x
4-Cl
1.3 [1.0, 1.6]
8.1 [7.2, 9.1]
0.76 [0.67, 0.86]
> 20
3’,4’-(OCH2O)
4’-CO2CH3
4’-CO2H
6.1 [4.9, 7.7]
4-Cl
6y
> 20
6j
5-CF3
5-CF3
5-CF3
5-CF3
5-CF3
5-CH3
5-CH3
6z
0.72 [0.56, 0.92]
0.46 [0.30, 0.71]
2.2 [1.7, 2.9]
6kc
6lc
6m
6n
6ob
6p
4’-OH
6aa
6bb
6cc
6dd
6ee
6ff
3’,4’-(OCH2O)
4’-CO2CH3
4’-CO2H
3’-CONH2
4’-CONH2
4’-CO2H
9.9 [7.3, 14]
1.1 [0.99, 1.3]
0.47 [0.39, 0.55]
1.0 [0.69, 1.5]
0.41 [0.36, 0.48]
6-Cl
6-Cl
0.12 [0.10, 0.14]
0.42 [0.35, 0.51]
0.063 [0.029, 0.14]
0.041 [0.034, 0.049]
6-F
4’-CO2CH3
3’,4’-(OCH2O)
4’-CO2H
6-F
3’-CH2OH, 4’-F
3’,4’-(OCH2O)
6-F
[a] Reagents and Conditions: (a) i. NaOH, I2, MeOH, rt, 24 h, 90-95%; ii. Boc2O, rt, 16 h.; (b) Ar-B(OH)2, PdCl2(dppf)·DCM, K3PO4, H2O, 1,4-Dioxane, 90 °C, 1.5 h.,
50-70%. [b] Compounds were purchased from ChemBridge. [c] Compound has a Boc-group on the indazole N-1 position.
MEK kinase. In general, compounds had the greatest selectivity
against MEK5, 2, and 3. In particular, compound 6ff displays
excellent selectivity across the entire MEK family. This compound
is at least 150-fold more potent against MEK4 than any other
MEKkinase, and is at least 385-fold selective against three other
MEK kinases.
Because compound 6ff was a potent and selective (among the
MEK family) MEK4 inhibitor in the functional assay, it was
evaluated against 57 diverse kinases (see supporting information
both fully inhibited MEK4. Because both compounds fully inhibited
MEK4 at the tested concentration of 10 µM and 6ff is 3-4 fold
more potent than 6a, it is possible that 6ff may be more selective
than compound 6a when both compounds are tested at
concentrations that give equivalent MEK4 inhibition. Additional
work to further define and improve the kinase selectivity of our
lead series is underway.
A preliminary evaluation of the cellular efficacy of 6ff was
performed to investigate the potential involvement of MEK4 in
cancer cell motility and migration. The results from a wound
scratch assay showed that compound 6ff had no efficacy at the
concentrations tested (10 and 25 µM).[10b] Interestingly,
compound 6ee has modest efficacy at 10 µM and performs better
at 25 µM, though never achieving the effect of control compound
genistein (see Table S2), suggesting differences in cell
permeability between the negatively-charged 6ff carboxylate and
the 6ee ether may be relevant. A trypan blue exclusion for cells
treated for 3 days to look at effects on proliferation and viability
was also performed (see Figure S2). Interestingly, it was
observed that both compounds (6ff and 6ee) had less toxicity
Table S1). These kinases were chosen to be
a highly
representative set of the broader kinome in accordance with
recent work showing this approach provides an efficient way in
which to assess overall kinase selectivity while minimizing
experimentation.[16] In addition to the 50 kinases from the diversity
panel,[16] the 7 MEK family members were also included. The
original hit (6a) was also evaluated to allow comparison. Inhibitor
6a was found to have an S(35) value of 0.088, meaning that it
inhibited 8.8% of tested kinases > 35%, which in our case was 5
out of 57 kinases tested. Inhibitor 6ff had an S(35) of 0.21, or 12
out of the 57 kinases. Both compounds were tested at 10 µM and
4
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10.1002/cmdc.201900019
ChemMedChem
COMMUNICATION
compared to the promiscuous kinase inhibitor genistein (with p
values < 0.05 when comparison of 6ff and 6ee against genistein
Financial support for this work was provide by the National Cancer
Institute (NCI) (R01 CA188015) and the Chicago Biomedical
Consortium. K. Deibler thanks the National Science Foundation
(NSF) for graduate research fellowship (DGE-1324585). A part of
this work was performed by the Northwestern University High
Throughput Analysis Laboratory (NU-HTA), and the Medicinal
and Synthetic Chemistry Core (ChemCore) at the Center for
Molecular Innovation and Drug Discovery (CMIDD), which is
funded by the Chicago Biomedical Consortium with support from
The Searle Funds at The Chicago Community Trust and Cancer
Center Support Grant P30 CA060553 from the National Cancer
Institute awarded to the Robert H. Lurie Comprehensive Cancer
Center.
Table 2. MEK family profiling. All data are IC50 values in µM.
MEK Isoform
MEK
4
MEK
4
ID
1
2
3
5
6
7
(p38)
(Jnk)
6a
6b
6j
0.18
0.92
0.25
0.13
0.39
0.11
0.21
0.20
0.18
0.36
0.26
0.066
0.46
0.88
0.24
0.06
0.75
0.56
0.41
0.51
0.22
0.10
1.5
7.2
11
> 27
15
16
> 27
> 27
> 27
> 27
> 27
16
10
8.3
12
>27
2.3
2.9
6.0
8.5
5.5
4.1
12
21
4.6
10
5.3
1.6
6.0
3.4
3.2
2.2
2.1
8.7
8.8
5.8
11
2.2
2.0
4.9
6.1
5.4
3.7
11
6n
6o
6p
6q
6r
> 27
5.4
Keywords: mitogen-activated protein kinase kinase 4 • MEK4 •
4.0
6.6
7.7
3.9
17
MAP2K4 • indazoles
9.1
References:
7.2
25
[1]
a) C.-T. Hsueh, D. Liu, H. Wang, Biomarker Res. 2013, 1, 1;
b) C. Wellbrock, I. Arozarena, Frontiers in cell and
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hematology & oncology 2013, 6, 27; f) B. B. Friday, A. A. Adjei,
Clinical Cancer Research 2008, 14, 342-346.
6.1
19
6s
6z
6ee
6ff
> 27
> 27
9.3
> 27
0.35
> 27
> 27
17
>27
21
6.9
14
6.6
15
0.10
> 27
>27
12
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10.1002/cmdc.201900019
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Entry for the Table of Contents
MEK4 is overexpressed and induces metastasis in advanced prostate cancer lesions. Herein we leveraged a MEK kinase platform
we previously developed, for mapping the pharmacological relatedness of MEK kinase family members, to identify new potent and
selective MEK4 inhibitors. We utilized computational docking, in vitro testing and preliminary cellular data to guide the optimization of
this novel series of compounds as the first of its kind in both activity and selectivity.
7
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