Highly functionalized terpyridines as competitive inhibitors of AKAP-PKA interactions

Article abstract of DOI:10.1002/anie.201304686

A good fit: Interactions between A-kinase anchoring proteins (AKAPs) and protein kinaseA (PKA) play key roles in a plethora of physiologically relevant processes whose dysregulation causes or is associated with diseases such as heart failure. Terpyridines have been developed as α-helix mimetics for the inhibition of such interactions and are the first biologically active, nonpeptidic compounds that block the AKAP binding site of PKA.

Full text of DOI:10.1002/anie.201304686

Angewandte
Chemie
DOI: 10.1002/anie.201304686
Peptide Inhibitors
Highly Functionalized Terpyridines as Competitive Inhibitors of
AKAP–PKA Interactions**
´
Gesa Schꢀfer, Jelena Milic, Adeeb Eldahshan, Frank Gçtz, Kerstin Zꢁhlke, Christian Schillinger,
Annika Kreuchwig, Jonathan M. Elkins, Kamal R. Abdul Azeez, Andreas Oder,
Marie C. Moutty, Nanako Masada, Monika Beerbaum, Brigitte Schlegel, Sylvia Niquet,
Peter Schmieder, Gerd Krause, Jens Peter von Kries, Dermot M. F. Cooper, Stefan Knapp,
Jçrg Rademann, Walter Rosenthal, and Enno Klussmann*
Protein kinase A (PKA) is a ubiquitous kinase that phos-
phorylates a broad variety of substrates. A-kinase anchoring
proteins (AKAPs) confer specificity to PKA signaling by
tethering the kinase to distinct cellular compartments,
thereby limiting the access of PKA to a defined pool of its
substrates.[1] Interactions between AKAPs and PKA play key
roles in a plethora of physiologically relevant processes such
as arginine-vasopressin (AVP) mediated water reabsorption
in renal principal cells; AVP triggers PKA phosphorylation of
the water channel aquaporin-2 (AQP2). AQP2 then redis-
tributes from intracellular vesicles into the plasma membrane,
thereby facilitating water reabsorption from primary urine.
The redistribution only occurs if PKA interacts with
AKAPs.[2] Dysregulation of cellular processes that depend
on AKAP–PKA interactions causes or is associated with
diseases.[1b,3] For example, in heart failure, elevated AVP
levels contribute to the excessive water retention by the
above-described mechanism. Cardiac myocyte contractility is
decreased in the failing heart; the control of contractility
crucially depends on AKAP–PKA interactions.[4]
domains of R subunit dimers and the RII binding domain
(RBD) of AKAPs. Dimerized D/D domains form a hydro-
phobic pocket that directly interacts with the 14–25 amino
acid long a-helical RBD.[5] Synthetic peptides derived from
RBDs of different AKAPs bind R subunits with nanomolar
affinity, for example, AKAP18d-L314E from AKAP18d
(KD = 4 nm; see Figures S1 and S2 as well as Table S2 in the
Supporting Information).[6] Such peptides effectively inhibit
AKAP–PKA interactions.[1] For example, membrane-perme-
able versions of AKAP18d-L314E[7] and Ht31[2a] (from
AKAP-Lbc) abolish the AVP-induced redistribution of
AQP2 in cultured principal cells. Thus disruption of
AKAP–PKA interactions even appears beneficial for the
treatment of diseases, such as heart failure, that are associated
with AVP-dependent excessive water retention.[3]
As a consequence of their generally low membrane
permeability and stability, peptides have limitations with
regard to their use in cell and animal studies and for drug
development. Small molecules and nonpeptide helix mimetics
are considered as alternatives to peptides, and thus the small
molecule FMP-API-1 was developed that inhibits AKAP–
PKA interactions. However, FMP-API-1 also activates PKA,
which suggests that it causes side effects in complex systems
such as whole animals.[8]
PKA holoenzyme is a tetramer consisting of a dimer of
regulatory (RIa, RIb, RIIa, or RIIb) and two catalytic (C)
subunits each bound to an R protomer. Upon binding of
cAMP to the R subunits, the C subunits dissociate and
phosphorylate their substrates. Interactions of PKA with
AKAPs are mediated by the dimerization/docking (D/D)
Nonpeptide helix mimetics including terphenyl and ter-
pyridine scaffolds[9] mimic a-helixes by presenting amino acid
[+]
[*] Dr. G. Schꢀfer,[+] Dr. J. Milic, Dr. A. Eldahshan, Dr. F. Gçtz,
Prof. J. Rademann
´
Dr. K. Zꢁhlke, A. Oder, Dr. M. C. Moutty, S. Niquet,
Dr. J. P. von Kries, Prof. Dr. W. Rosenthal,
Priv.-Doz. Dr. E. Klussmann
Free University Berlin, Institut fꢁr Pharmazie
Kçnigin-Luise-Strasse 2+4, 14195 Berlin (Germany)
[+] These authors contributed equally to this work.
Max Delbrꢁck Center for Molecular Medicine (MDC)
Robert-Rçssle-Strasse 10, 13125 Berlin (Germany)
E-mail: enno.klussmann@mdc-berlin.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(DFG KL1415/4-2, RA895/5-2). J.E., K.A.A., and S.K. were supported
by the Oxford Structural Genomics Consortium (SGC), a charity
(number 1097737) receiving funds from AbbVie, Boehringer
Ingelheim, the Canada Foundation for Innovation, the Canadian
Institutes for Health Research, Genome Canada, GlaxoSmithKline,
Janssen, Lilly Canada, the Novartis Research Foundation, the
Ontario Ministry of Economic Development and Innovation, Pfizer,
Takeda, and the Wellcome Trust [092809/Z/10/Z]. AKAP=A-kinase
anchoring protein, PKA=protein kinase A.
C. Schillinger, A. Kreuchwig, M. Beerbaum, B. Schlegel,
Dr. P. Schmieder, Dr. G. Krause, Prof. J. Rademann
Leibniz-Institut fꢁr Molekulare Pharmakologie
Robert-Rçssle-Strasse 10, Berlin (Germany)
Dr. J. M. Elkins, K. R. Abdul Azeez, Prof. Dr. S. Knapp
Nuffield Department of Clinical Medicine, Structural Genomics
Consortium and Target Discovery Institute University of Oxford
Old Road Campus Research Building
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304686.
Roosevelt Drive, Oxford, OX3 7DQ (UK)
N. Masada, Prof. D. M. F. Cooper
Department of Pharmacology
Tennis Court Rd., Cambridge (UK)
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derived side chains from a rodlike axis and are expected to
combine the desired properties of peptides, that is, specificity/
target selectivity, and those of small molecules, that is,
stability and membrane permeability. We developed poly-
pyridines as helix mimetics of peptide AKAP18d-L314E,[10]
taking into account the favorable solubility, conformational
orientation, and biological activity of helix mimetics of this
class. The starting point was an interaction model in which
hydrophobic residues (L301, L304, L308) of the peptide
interact with the hydrophobic bottom of the D/D domain
dimer of RIIa and where the hydrophilic side chains such as
of E300 of the peptide interact with hydrophilic residues such
as Q4 at the peripheral rim of the cavity formed by the D/D
dimer.[6] Several terpyridines, 1a–f (Schemes 1 and 4), were
Scheme 2. Synthesis of bipyridyl bromides 6a,b, the building blocks
for the final coupling reaction. TMP=2,2,6,6-tetramethylpiperidide.
The ortho-borylation of cyanopyridines 5 was adapted for
the synthesis of the first pyridyl building block—the diiso-
propylboronic acid ester 2. An ortho-directed metalation
reaction (DoM) involves the cyano function, which reacts
with the first equivalent of LiTMP as base and most likely
forms a lithiun amidinate that serves as the donor-metalation
group (DMG) and directs deprotonation to the C3-site of the
pyridine ring by the second equivalent of base.[12] A third
equivalent of the base was required for effective metalation,
presumably to transform the aliphatic ester into the enolate
and thereby also protecting the neighboring benzylic position
from deprotonation. The addition of four equivalents of the
base increased the yield without any side reaction. Since the
isolation of the diisopropylboronic ester was not possible and
isolation of the boronic acid was associated with protode-
boronation, we esterified the acid in situ by adding pinacol to
the reaction mixture.[13] Synthesis of ester 2 required adding
pinacol and heating the reaction mixture to 408C (Scheme 2).
The Pd-catalyzed coupling of 2,5-dibromo-3-methylpyri-
dines 3a,b and crude boronic acid ester 2 was carried out in
the presence of potassium phosphate and yielded bipyridines
6a,b in low amounts. When boronic acid ester 2 was added
slowly through a dropping funnel over 90 min, the yield
increased to 74% (Scheme 2).
The cyclopentapyridine moiety of building blocks 4a,b
was synthesized by a RhII-catalyzed [2+2+2] cycloaddition of
1,6-heptadiyne (7) with succinonitrile (8; Scheme 3).[14]
Reducing the nitrile moiety with borane-dimethyl sulfide
led to amine 10. Monobenzylated amine 10-Bn was obtained
by reductive amination followed by dibenzylation with Et3N
as the base. The mixed lithium base aggregates approach was
used for the regioselective halogenation at the C1-position of
cyclopentapyridine 11a.[15] No conversion of the starting
material occurred when n-hexane was used as the solvent for
the lithiation;[15] only the addition of diethyl ether as a co-
solvent during the metalation process led to the formation of
4a,b. CBr4 and C2Cl6 were used as electrophiles. Since the
chlorination was more efficient, the final cross-coupling
reaction was optimized using pyridyl chlorides 4a,b.
Scheme 1. Planned synthesis of terpyridines 1a–f by a sequence of
Suzuki coupling reactions.
designed in silico as synthetic targets. The hydrophobic phase
of the AKAP18d-L314E helix in molecule 1b corresponds to
the meta-methyl group of the second pyridine ring, the
condensed cyclopentyl ring of the third pyridine moiety, and
the following two benzyl rings. Thus, they interact with the
hydrophobic core (yellow in Figure 4 and Figure S1 in the
Supporting Information) of the binding cavity. Other sub-
stituents address hydrophilic residues of the rim at the D/D
domain such as the carboxy group of the external pyridine
ring that mimics the side chain of E300 and is likely to interact
with Q4 of the D/D domain.
The synthesis of the potential ligands 1a–f involved two
successive Suzuki cross-coupling reactions of 2,5-dibromo-
pyridines 3a,b (Scheme 2). The key to this strategy was the
distinctive reactivity of the 2-bromo and 5-bromo substitu-
ents, which allowed for the regioselective Suzuki coupling of
the dibromides 3a,b.[11]
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Scheme 4. Synthesis of the terpyridines 12a, 12b, and 12c by micro-
wave-assisted, “one-pot” Suzuki–Miyaura coupling followed by base-
or acid-catalyzed hydrolysis to the terpyridylpropionic acids 1a–f.
Reagents and conditions: a) NaOH, EtOH/H2O, 858C, 4 h; b) 6m
HCl, EtOH, 958C, 1 h; c) NaOH, EtOH/H2O, 858C, 1 h. dba=trans,-
trans-dibenzylideneacetone, MW=microwaves.
reduced to one hour (Scheme 4, conditions c). Acid-catalyzed
hydrolysis furnished the expected dicarboxylic acids 1b and
1d (Scheme 4, conditions b).
The binding of the new compounds to the D/D domain
was evaluated in 15N-SOFAST-HMQC experiments.[17] Com-
pounds 1a–f caused similar shifts or disappearances of signals
as the peptides derived from AKAP18d, thus indicating that
they bind to the same site on the D/D domain (see the
Supporting Information).
Isothermal titration calorimetry revealed that 1b and 1 f
bind to the D/D domain with an estimated KD = 148 mm and
KD = 31 mm, respectively (Figure 1). The binding is mainly
driven by a large positive entropy change, presumably
because of the release of water molecules from the binding
interface. Compound 1d bound to the D/D with a KD value
similar to that of 1 f (10–60 mm). However, the calorimetric
data were of lower quality because of the small enthalpy
change associated with this binding event (see Figure S4 in the
Supporting Information).
Scheme 3. Synthesis of cyclopentapyridyl chlorides 4a,b.
The synthesis of cyclopentapyridine 11b requires the
separate introduction of the two different benzyl moieties.
The secondary amine was obtained under harsh base con-
ditions using NaOH, whereby the substituted benzyl group
was introduced in a microwave-assisted aqueous N-alkyla-
tion.[16] Surprisingly, the employment of four equivalents of Li
base was not sufficient for the lithiation of pyridine 4a (59%
yield); increasing amounts of the base raised the yield of
chloride 4b fourfold to 78%.
We developed a microwave-assisted “one-pot” procedure
for the Suzuki–Miyaura coupling reaction for synthesis of
À
terpyridines 12a,b. For this, the borylation and C C coupling
The influence of our compounds on AKAP–PKA inter-
actions was determined quantitatively in homogeneous time-
resolved fluorescence (HTRF) assays. HTRF measurements
(at pH 7) with the D/D domain of RIIa and AKAP18a
revealed that 1b and 1e decreased the FRET signal and thus
inhibited the interaction (IC50 = 38 mm and 138 mm, respec-
tively; Figure 2). As expected, the peptide AKAP18d-L314E
inhibited the interaction at a nanomolar concentration
(12.7 nm),[6] while the inactive control peptide AKAP18d-PP
did not affect the interaction (Figure 2). The inhibitory
potency of 1a and 1 f was too low to determine IC50 values.
Next, we examined the ability of 1b to interfere with
AKAP–PKA interactions in cells. HEK293 cells possess
a negative feedback loop for terminating prostaglandin E1
(PGE1) induced cAMP synthesis, a pathway that depends on
AKAP–PKA interactions. Stimulation of the cells with PGE1
leads to activation of adenylyl cyclase and the synthesis of
reactions were optimized in terms of solvent, Pd0 catalyst,
phosphine ligand, and reaction temperature. The best yields
(12a = 46%, 12b = 50%) were obtained with [Pd2(dba)3] as
the Pd0 source in combination with XPhos as a ligand and
using dioxane as solvent. The use of aqueous potassium
phosphate as a base was more effective than potassium
carbonate. The borylation step resulted in complete con-
sumption of the starting material when KOAc was used as the
base, whereas the cross-coupling demanded the addition of
a stronger base.[15] The last step of the synthesis was
a hydrolysis of 2-cyanoterpyridines 12a,b. Unexpectedly, the
base-catalyzed hydrolysis (Scheme 4, conditions a) led to only
partial hydrolysis of the nitrile function. The amidoterpyr-
idylpropionic acids 1a and 1c were obtained from the ethyl
esters 12a and 12b, respectively. The cyanoterpyridylpro-
pionic acid 1e was obtained when the hydrolysis time was
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Figure 3. HEK293 cells were transfected to express cAMP-dependent
cyclic nucleotide-gated channels (CNGC) and loaded with the Ca2+
indicator Fura-2. The cells were left untreated, incubated with the PKA
inhibitor H89, FMP-API-1, or compounds 1a or 1b (each 20 mm) for
30 min. The cells were stimulated with prostaglandin E1 (PGE1) to
trigger cAMP synthesis at a time point of 60 s. cAMP opens the
CNGCs, and then Ca2+ enters the cells and binds to Fura-2. This
binding generates fluorescence signals, which were imaged. Numbers
in brackets indicate the numbers of individual cells measured.
Figure 1. Isothermal titration calorimetric measurements for determi-
nation of the KD values for interactions of 1b and 1 f with the D/D
domain of RIIa. Measurements consisted of successive 10 mL injec-
tions of the D/D domain into a less concentrated solution of
compound in a MicroCal VP-ITC instrument, with 1.0 mm D/D domain
and 0.05 mm 1b, or 0.6 mm D/D domain and 0.03 mm 1 f. The data
were fitted to a one-site binding model.
PKA interactions in cells (Figure 3). Although 1a binds to the
D/D domain (see Figure S3 in the Supporting Information), it
did not interfere with the feedback inhibition, presumably
because it does not reach sufficient concentrations in cells.
The terpyridines do not inhibit the catalytic activity of PKA.
We have developed a set of terpyridines as a-helix
mimetics of the PKA anchoring disruptor peptide
AKAP18d-L314E. Similar to the original peptide, the com-
pounds bind to the D/D domain of RII subunits of PKA. One
of them, 1b, is the first nonpeptidic agent that binds to the D/
D domain of RII subunits and inhibits AKAP–PKA inter-
actions in vitro as well as in vivo. A model of the interaction is
depicted in Figure 4. Evaluation of the structure–activity
relationship (SAR) indicates that a COOH group as R2 in 1b
is critically involved in defining its inhibitory potency; NH2, as
in 1a, is not tolerated at this position. Both H and OMe seem
to be tolerated as R1, as 1b and 1e inhibit AKAP–PKA
interactions (Figure 2). However, the influence of CN as R2 in
Figure 2. Compounds 1b and 1e and peptide AKAP18d-L314E inhibit
the interaction of the D/D domain of RIIa with AKAP18a. AKAP18a
lacks the 10 N-terminal amino acid residues which encode the
membrane-targeting domain. Peptide AKAP18d-PP represents the RII
binding domain of AKAP18d, but contains two proline residues which
prevent interaction with the D/D domain. This peptide does not affect
the interaction.[6] Homogeneous time-resolved fluorescence (HTRF)
assays were carried out using the proteins in concentrations of 50 nm
each.
cAMP; cAMP activates PKA, which phosphorylates cAMP
phosphodiesterase PDE4D and thereby increases PDE
activity and thus inhibits cAMP accumulation. PDE4D is
phosphorylated by PKA bound to the AKAP gravin.[18] In
addition, AKAP150 tethers PKA to adenylyl cyclase and
facilitates PKA phosphorylation of the cyclase and thus its
inactivation.[19] Disruption of AKAP–PKA interactions with
peptides (Ht31), the small molecule FMP-API-1, or by PKA
inhibition with H89 prevents the PGE1-dependent negative
feedback and maintains high adenylyl cyclase activity in the
presence of PGE1.[8,18,19] 1b also inhibits the feedback
inhibition, thus indicating that it interferes with AKAP–
Figure 4. Model of the interaction between terpyridine 1b (cyan) and
the D/D domain of human regulatory RIIa subunits of PKA. The
primary structure of the D/D domain is SHIQIPPGLTELLQGYT-
VEVLRQQPPDLVEFAVEYFTRLREAR (gene bank entry accession
NP_004148); the residues of the pocket are shown with side chains
and a translucent surface (yellow: hydrophobic, blue: hydrophilic). The
binding pocket is rather hydrophobic (I5, P6, L9, T10, L13, T17, L21)
and contains the possible hydrogen-bond donors Q4 and Q14 at the
rim (blue); Q4 and Q14 are predicted to interact with the carboxy
groups of the terpyridine moiety of 1b. For details see the Supporting
Information.
4
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1e is not clear. The COOH group as R2 allows for the
synthesis of more derivatives and thereby provides the basis
for novel high affinity compounds to disrupt AKAP–PKA
interactions. These SAR data together with our NMR data
support a model of the interaction of 1b with the D/D domain
of RIIa subunits (Figure 4) in which 1b assumes a conforma-
tion that mimics the a-helical AKAP18d fragment that
interacts with the D/D domain (see Figure S1 in the Support-
ing Information).
In summary, the new terpyridine scaffolds represent the
first biologically active and nonpeptidic compounds that
block the binding site of AKAPs on regulatory subunits of
PKA and interfere with AKAP–PKA interactions.
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Keywords: AKAP · peptide mimetics · protein kinase A · protein–
protein interactions · Suzuki coupling · terpyridines
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Communications
Peptide Inhibitors
A good fit: Interactions between A-kinase
anchoring proteins (AKAPs) and protein
kinase A (PKA) play key roles in a plethora
of physiologically relevant processes
whose dysregulation causes or is associ-
ated with diseases such as heart failure.
Terpyridines have been developed as a-
helix mimetics for the inhibition of such
interactions and are the first biologically
active, nonpeptidic compounds that
block the AKAP binding site of PKA.
´
G. Schꢁfer, J. Milic, A. Eldahshan, F. Gçtz,
K. Zꢂhlke, C. Schillinger, A. Kreuchwig,
J. M. Elkins, K. R. Abdul Azeez, A. Oder,
M. C. Moutty, N. Masada, M. Beerbaum,
B. Schlegel, S. Niquet, P. Schmieder,
G. Krause, J. P. von Kries,
D. M. F. Cooper, S. Knapp, J. Rademann,
W. Rosenthal,
E. Klussmann*
&&&& — &&&&
Highly Functionalized Terpyridines as
Competitive Inhibitors of AKAP–PKA
Interactions
6
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