Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway

Article abstract of DOI:10.1002/anie.201810312

Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

Full text of DOI:10.1002/anie.201810312

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201810312
German Edition: DOI: 10.1002/ange.201810312
Biological Activity
Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase
Inhibitors and Effective Modulators of the Hedgehog Pathway
ˇ
ˇ
Vꢀclav Nemec, Michaela Hylsovꢀ, Lukꢀs Maier, Jana Flegel, Sonja Sievers, Slava Ziegler,
ˇ
Martin Schroeder, Benedict-Tilman Berger, Apirat Chaikuad, Barbora Valcꢁkovꢀ,
ˇ
Stjepan Uldrijan, Stanislav Drꢀpela, Karel Soucek, Herbert Waldmann, Stefan Knapp, and
Kamil Paruch*
Abstract: Reported is the identification of the furo[3,2-
b]pyridine core as a novel scaffold for potent and highly
selective inhibitors of cdc-like kinases (CLKs) and efficient
modulators of the Hedgehog signaling pathway. Initially,
a diverse target compound set was prepared by synthetic
sequences based on chemoselective metal-mediated couplings,
including assembly of the furo[3,2-b]pyridine scaffold by
copper-mediated oxidative cyclization. Optimization of the
subseries containing 3,5-disubstituted furo[3,2-b]pyridines
afforded potent, cell-active, and highly selective inhibitors of
CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisub-
stituted furo[3,2-b]pyridines revealed sub-micromolar modu-
lators of the Hedgehog pathway.
drug discovery.[2] As numerous major post-translational
signaling mechanisms in the cell rely on phosphorylation,
protein kinases represent one of the therapeutically most
important target classes.[3] Modulation of kinase activity can
be utilized in modern anticancer therapy as well as in the
treatment of other diseases. Currently over 40 small-molecule
protein kinase inhibitors have been approved by the FDA for
clinical use.[4] While the biological functions of few protein
kinases have been thoroughly explored, the role of many
others in signaling and their potential as drug targets is largely
unexplored. Identification of potent and selective modulators
of these kinases as chemical probes for functional studies (and
as potential starting points for medicinal chemistry optimiza-
tion) is therefore of significant importance.[5]
S
mall molecules represent the majority of clinically profiled
The majority of small-molecule protein kinase inhibitors
are ATP mimetics, frequently containing heteroaromatic
bioisosteres of purine. Interestingly, similar scaffolds can
yield inhibitors with significantly different inhibitory activity.[6]
While pyrazolo[1,5-a]pyrimidine represents a privileged scaf-
fold,[7] kinase inhibitors possessing analogous furo[3,2-b]pyr-
idine motif are very rare, as they are not typical ATP mimetic
moieties. To date, only few examples of this scaffold have
been published with a rather narrow substitution pattern.[8] In
this report, we describe the identification of the furo[3,2-
b]pyridine core as the central scaffold for two novel structur-
ally related compound classes with distinct biological activity:
highly selective inhibitors of cdc-like kinases (CLKs) and
potent modulators of the Hedgehog pathway.
compounds[1] and identification of privileged scaffolds appli-
cable in the synthesis of compounds with specific biological
activity thus represents a key tool in chemical biology and
ˇ
[*] V. Nemec, Dr. M. Hylsovꢀ, Dr. L. Maier, Prof. Dr. K. Paruch
Department of Chemistry, CZ-Openscreen
Masaryk University
Kamenice 5, Brno, 625 00 (Czech Republic)
E-mail: paruch@chemi.muni.cz
ˇ
ˇ
V. Nemec, Dr. M. Hylsovꢀ, Dr. L. Maier, B. Valcꢁkovꢀ, Dr. S. Uldrijan,
ˇ
S. Drꢀpela, Dr. K. Soucek, Prof. Dr. K. Paruch
International Clinical Research Centre
St. Anne’s University Hospital
ˇ
Pekarskꢀ 53, Brno, 656 91 (Czech Republic)
Initially, we prepared a small library of structurally diverse
target compounds consisting of 3,5-disubstituted, 5,7-disub-
stituted and 3,5,7-trisubstituted furo[3,2-b]pyridines (7;
Scheme 1).
J. Flegel, Dr. S. Sievers, Dr. S. Ziegler, Prof. Dr. H. Waldmann
Max-Planck-Institute fꢂr Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Assembly of the furo[3,2-b]pyridine core by precedented
intramolecular Heck[9] and Sonogashira[10] reactions pro-
ceeded uneventfully and provided the intermediates 2 and
4. The compound 2 was converted into 3 (Scheme 1). Of note,
chlorination of the N-oxide intermediate provided a signifi-
cant part of the 2-chloro regioisomer. For compounds lacking
substituents at position 3 (e.g., the desilylated N-oxide of 5;
see compound S6 in the Supporting Information), the
chlorination was even more problematic and it exclusively
yielded the undesired 2-chloro isomer. In contrast, chlorina-
tion of the TMS-containing N-oxide of 5 (see compound S7)
proceeded well and ultimately provided the desired 6 in good
yield. Final amination and Suzuki couplings with the chlorides
M. Schroeder, B. T. Berger, Dr. A. Chaikuad, Prof. Dr. S. Knapp
Institute for Pharmaceutical Chemistry
Structural Genomics Consortium
Johann Wolfgang Goethe-University
Max-von-Laue-Strasse 15, 60438 Frankfurt am Main (Germany)
ˇ
B. Valcꢁkovꢀ, Dr. S. Uldrijan
Department of Biology, Faculty of Medicine
Masaryk University
Kamenice 5, Brno, 625 00 (Czech Republic)
ˇ
S. Drꢀpela, Dr. K. Soucek
Department of Cytokinetics, Institute of Biophysics CAS
Krꢀlovopolskꢀ 135, Brno, 612 65 (Czech Republic)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201810312.
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The synthesis of furo[3,2-b]pyridines with (hetero)aryls
directly attached to position 3 proved more challenging. This
particular compound class was neither known at that point
nor available by directly applicable synthetic route. However,
we were able to prepare the desired chloro compounds 9
(Scheme 1) using a slightly modified version of the Cu-
mediated cyclization reported for benzofurans,[11] and sub-
sequently converted these cyclization products into the
corresponding target compounds 7a–h (Table 1).
The three routes depicted in Scheme 1 provided a starting
library of 20 compounds, and they were profiled against
a panel of 206 human protein kinases at 1 mm concentration
(Eurofins). In addition, IC50 values of the compounds 7i–k
and 7m–o, analogues of known pyrazolo[1,5-a]pyrimidine-
based inhibitors of CDK2[12] and PIM[13] kinases, were also
determined. The CDK2 and PIM furo[3,2-b]pyridine inhib-
itors 7i–k and 7m–o were significantly less potent than the
corresponding pyrazolo[1,5-a]pyrimidines (see Table S1A
and S1B in the Suppporting Information). However, broad
kinase panel profiling revealed that 7c possesses attractive
activity against members of the CLK and HIPK family
(Table 1; see Tables S2 and S3).
CLK kinases regulate alternative mRNA splicing but
their precise role in this process is poorly understood,[14] and
CLK2 is an emerging therapeutic target in oncology.[15] To
unravel the role of CLK kinases in splicing, selectivity of
chemical inhibitors within the highly conserved splicing
kinases subfamily, which includes CLKs, DYRKs, and
Scheme 1. Synthesis of an initial library of the substituted furo[3,2-
b]pyridines 7 and modular assembly of the CLK inhibitors 12.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, dppf=1,1’-bis(diphenylphos-
phanyl)ferrocene, mCPBA=m-chloroperbenzoic acid, TEA=triethyl-
amine, TMS=trimethylsilyl.
3 and 6 provided subsets of the compound 7 with N- and C-
linked substituents at position 7.
Table 1: IC50 values[a] for the selected compounds 7a–h (R7 =H) and 12a–j.
[a] All compounds were tested at Eurofins. Additional compounds are listed in Table S2.
2
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SRPKs, would be required. However, the few reported
examples of specific inhibitors for splicing kinases often
retain dual activities of CLK and DYRK activity,[16] reflecting
their highly conserved ATP binding pocket. We were
intrigued by the lack of activity of the hit 7c for the closely
related DYRKs, whose inhibition may not always be ther-
apeutically desirable,[17] and its exclusive selectivity within the
splicing kinases for the CLKs. We thus steered the subsequent
structure–activity relationship (SAR) optimization towards
the development of potent and selective CLK inhibitors.
By the third route depicted in Scheme 1, we prepared an
additional set of (16) 3,5-disubstituted furo[3,2-b]pyridines.
For position 5, the 1-methyl-1H-pyrazol-4-yl motif was
identified as optimal, whereas relatively large substituents
(e.g. 2-naphthyl in compound 7 f) were preferred at position 3
(Table 1; see Table S2).
Since the most active hits contained (hetero)aryls at
positions 3 and 5 of the furo[3,2-b]pyridine scaffold, we
focused on the SAR development within this subseries. We
envisioned that chemoselective manipulation of properly 3,5-
dihalogenated furopyridines could provide a rapid and
flexible access to these target compounds. However, Suzuki
couplings of known the 3-bromo-5-chlorofuro[3,2-b]pyri-
dine[18] under a variety of reaction conditions provided only
practically inseparable mixtures of several components. For-
tunately, Pd-catalyzed chemoselective couplings with newly
prepared 3-bromo-5-iodofuro[3,2-b]pyridine (11) were suc-
cessful and provided the desired intermediates with (hetero)-
aryl substituents at position 5, and were finally converted into
the additional target compounds 12 (Scheme 1). Additional
analogues were flexibly prepared from the m-chlorophenyl
intermediate 13. Profiling of this set (59 compounds) revealed
additional SAR trends (Table 1; see Table S2): 1. Analogues
containing aromatic motifs with properly oriented substitu-
ents were found to be particularly active with high overall
selectivity (see Table S4); 2. In contrast, the CLK inhibitory
activity rapidly decreased upon increasing steric bulk (meth-
ylation) at positions 2, 6, or 7 (14–16); and also around the
heterocycle at position 5 (7g–h).
X-ray crystal structures of 12h, 12k, 12l, and 12m in
CLK1 (Figure 1A; see Figure S1) provided insight into the
binding mode of this unusual ATP mimetic furopyridine
scaffold and served as the basis for advanced SAR develop-
ment. All inhibitors showed a conserved binding mode with
CLK1 and, in contrast to most ATP competitive kinase
inhibitors, they were anchored to the back pocket rather than
the hinge region. The furo[3,2-b]pyridine served as only
a weak ATP mimetic forming a single hydrogen bond
between the furane oxygen and the main-chain L244, while
in the backpocket the methylpyrazole group interacted with
the catalytic Lys191. The structural data highlighted the
advantage of weak ATP mimetic hinge interaction for
selectivity: in comparison to the furo[3,2-b]pyridine 12j,
indeed, the stronger hinge binder pyrazolo[1,5-a]pyrimidine
analogue (S53) showed comparable activity against CLKs but
significantly worse selectivity (see Figure S2 and Table S5).
Kinome-wide screening and cell profiling revealed that
12 f was the most selective analogue with good activity in the
cell (cellular BRET for CLK1 IC50 = 51 nm; Figures 1B,C; see
Figure 1. Characterization of furo[3,2-b]pyridine derivatives in CLK1.
A) crystal structure reveals the binding mode of compound 12h in
CLK1 (pdb id 6I5I). B) Kinome tree representation of the selectivity of
the lead compound 12 f. % Inhibition in enzyme kinetic assays is
shown as sheres as indicated in the Figure capture. C) On-target
!
activity of 12 f in CLK1 determined by NanoBRET assay. for control
~
with no compound, and for background signal (see the Supporting
Information for method). D) Cytotoxicity of 12 f for the breast cancer
cell line MCF7. E) Modulation of alternative mRNA splicing of Mdm4
detected by PCR.
Tables S6 and S7). Activity against off-target HIPKs was
rather surprising, nonetheless in vitro kinase assays confirmed
greater than 20-fold weaker affinities than for CLKs. In
accordance with the previous reports on the role of CLKs in
the splicing process,[19] we observed that 12 f profoundly
affected the Mdm4 alternative splicing and showed high
activity in cytotoxicity assays using MCF7 breast cancer cells
(Figure 1D,E; see Table S8). In addition, 12 f also has
favorable pharmacokinetics (mouse, 10 mpk, IP: Cmax
=
1.24 mm, T1/2 = 58 min; no acute toxicity observed), suggesting
its potential use in in vivo models. Given its overall selectivity
profile as well as its cellular activities, 12 f can be considered
a quality probe[20] for CLK1, CLK2, and CLK4.
The observations summarized above served also as the
basis for the design of a kinase-inactive furo[3,2-b]pyridine
sub-library that was additionally profiled in a different
biological context to explore potential applications of this
series (see below). In addition, the set also contained
compounds that could be used as negative controls for
direct comparison for the on-target inhibitions of 12 f.
Specifically, we focused on manipulation of position 7,
installing C- and N-linked substituents to prevent interaction
with kinases. To produce target compounds 23, we further
utilized the route originally developed to prepare 16
(Scheme 2). Iodocyclization of the Sonogashira intermediate
17 provided 18, which was selectively manipulated at position
3 by Pd-catalyzed couplings. Of note, the regioselectivity of
the subsequent functionalization of position 7 again depended
on the presence of the protecting group at position 2, while
the TIPS-protected 19 was lithiated (and subsequently
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Scheme 2. Synthesis of kinase-inactive sub-series 23 by regioselective
lithiation. TBAF=tetra-n-butylammonium fluoride, TIPS=triisopropyl-
silyl.
methylated or iodinated) at position 7, the desilylated version
of 19 (i.e. compound 9b, R3 = 2-naphthyl) underwent lithia-
tion at position 2 and upon methylation provided the target
compound 14.
Investigation of activity in different cellular pathways
revealed that the compounds 23 are nontoxic sub-micromolar
inhibitors of the Hedgehog (Hh) pathway (see Table S9), and
are crucial for embryonic development and tissue regener-
ation.21 Binding of a Hh ligand to the transmembrane
receptor Patched1 (PTC1) leads to the abrogation of
Smoothened (SMO) suppression and its accumulation in the
primary cilium. Subsequently, GLI transcription factors
translocate into the nucleus and initiate the transcription of
Hh specific genes.[21] Aberrant activation of Hh signaling is
involved in medulloblastoma and basal cell carcinoma.[22] In
an osteoblast differentiation assay using C3H10T1/2 cells for
primary screening,[23,24] the most active compound, 23a
(Figure 2a), suppressed Hh-dependent osteogenesis with an
IC50 of 300 Æ 100 nm. In an orthogonal, GLI-dependent
reporter gene assay using Shh-LIGHT2 cells 23a inhibited
the GLI-mediated response with an IC50 of 400 Æ 100 nm
(Figure 2b). In accordance with this observation, reverse-
transcription quantitative PCR analysis (RT-qPCR) revealed
that 23a at a concentration of 0.5 mm reduces the expression
of the Hh target genes Gli1 and Ptch1 by 55% and 63%,
respectively (Figure 2c).
Figure 2. 23a inhibits Hh signaling: a) Structure of 23a. b) GLI-depen-
dent reporter gene assay. Shh-LIGHT2 cells were treated with 2 mm
purmorphamine and different concentrations of 23a or DMSO as
a control for 48 h prior to detection of Firefly (Fluc) and Renilla (Rluc)
luciferase activity. The signal of the GLI-responsive Firefly luciferase
was divided by the control signal of the Renilla luciferase. The value
for cells which were treated with purmorphamine and DMSO, was set
to 100%. Data are mean values of three biological replicates Æ SD.
c) RT-qPCR analysis of Hh target gene expression. NIH-3T3 cells were
treated with 2 mm purmorphamine and different concentrations of the
compound or DMSO as a control, for 48 h. After isolation of RNA and
reverse transcription, qPCR was performed using primer for Gli1 and
Ptch1 and Gapdh as a reference. Data were related to the value for
cells, which were treated with DMSO, which was set to 100%. Data
are mean values Æ SD (n=3). d) Quantitative SMO binding assay.
HEK293T cells ectopically expressing SMO-BFP were treated with 5 nm
BODIPY-cyclopamine and 23a (30 mm) or vismodegib (5 mm) and
DMSO as controls for 4 h. Cells were then analyzed by means of flow
cytometry to quantify the BODIPY-cyclopamine fluorescence. Data are
presented as the fraction of BODIPY-cyclopamine positive cells, of all
transfected cells (BFP-positive) and are mean values Æ SD of three
biological replicates. e) Qualitative SMO binding assay. HEK293T cells
ectopically expressing SMO were fixed and treated with 5 nm BODIPY-
cyclopamine (green) and 23a (30 mm) or vismodegib (5 mm) and
DMSO as controls. To visualize the nuclei, cells were stained with
DAPI (blue). Scale bar: 50 mm.
Most of the currently known Hh inhibitors target SMO.[25]
In a competition experiment with the SMO antagonist
BODIPY-cyclopamine, after treatment of cells with 30 mm
23a, BODIPY-cyclopamine related fluorescence was not
observed (Figure 2e). Quantitative analysis by flow cytom-
etry (Figure 2d) proved this observation, and confirmed 23a
as a SMO binder.
In the Thermo Fisher SelectScreen kinase panel (454
kinases), 23a inhibited only 5 kinases to 40–60% at 10 mm
concentration (see Table S10A and S10B). It can be thus
estimated that the corresponding IC50 values are at least
tenfold higher than the effective concentration of the com-
pound in the cell (Figure 2). Kinase off-target effects therefore
should not be responsible for the observed cellular activity.
In summary, our synthetic methodology enables modular
construction of furo[3,2-b]pyridines. Within the 3,5-disubsti-
tuted subseries we identified potent and highly selective
inhibitors of CLKs, exemplified by 12 f (MU1210). Activity of
this series could be also optimized for other kinases such as
HIPK and Haspin, as well as PIM which were identified as
targets in selectivity screens of some analogues.
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23a (MU1300), a new effective modulator of the Hedgehog
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Acknowledgements
The work was supported by the following grants: CZ-OPEN-
SCREEN: National Infrastructure for Chemical Biology
(Identification code: LM2015063), Preclinical Progression of
New Organic Compounds with Targeted Biological Activity
(CZ CZ.02.1.01/0.0/0.0/16_025/0007381), MUNI/E/0456/2018,
and the National Program of Sustainability II (MEYS CR,
project No. LQ1605). B-T.B., M.S., A.C., and S.K. are grateful
for support by the SGC, a registered charity supported by
AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada
Foundation for Innovation, Eshelman Institute for Innova-
tion, Genome Canada, Innovative Medicines Initiative (EU/
EFPIA) [ULTRA-DD 115766], Janssen, Merck KGaA,
MSD, Novartis Pharma AG, Ontario Ministry of Economic
Development and Innovation, Pfizer, S¼o Paulo Research
Foundation-FAPESP, Takeda, and Wellcome. A.C. is sup-
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Conflict of interest
The authors declare no conflict of interest.
Keywords: biological activity · chemical probes · heterocycles ·
inhibitors · kinases
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Manuscript received: October 3, 2018
Revised manuscript received: November 16, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Biological Activity
ˇ
V. Nemec, M. Hylsovꢁ, L. Maier, J. Flegel,
S. Sievers, S. Ziegler, M. Schroeder,
ˇ
B. T. Berger, A. Chaikuad, B. Valcꢂkovꢁ,
ˇ
S. Uldrijan, S. Drꢁpela, K. Soucek,
H. Waldmann, S. Knapp,
K. Paruch*
&&&& — &&&&
Core competence: The furo[3,2-b]pyridine
core has been identified as a novel scaf-
fold for potent and highly selective
inhibitors. A diverse target compound set
was prepared by synthetic sequences
based on chemoselective metal-mediated
couplings. The 3,5-disubstituted furo[3,2-
b]pyridine sub-series afforded potent,
cell-active, and highly selective inhibitors
of cdc-like kinases (CLKs). And the
kinase-inactive subset of 3,5,7-trisubsti-
tuted furo[3,2-b]pyridines afforded sub-
micromolar modulators of the Hedgehog
pathway.
Furo[3,2-b]pyridine: A Privileged Scaffold
for Highly Selective Kinase Inhibitors and
Effective Modulators of the Hedgehog
Pathway
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!