Small-Molecule Inhibition of the UNC119–Cargo Interaction

Article abstract of DOI:10.1002/anie.201701905

N-Terminal myristoylation facilitates membrane binding and activity of proteins, in particular of Src family kinases, but the underlying mechanisms are only beginning to be understood. The chaperones UNC119A/B regulate the cellular distribution and signal

Full text of DOI:10.1002/anie.201701905

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Communications
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International Edition: DOI: 10.1002/anie.201701905
German Edition: DOI: 10.1002/ange.201701905
Medicinal Chemistry
Small-Molecule Inhibition of the UNC119–Cargo Interaction
Tom Mejuch, Guillaume Garivet, Walter Hofer, Nadine Kaiser, Eyad K. Fansa, Christiane Ehrt,
Oliver Koch, Matthias Baumann, Slava Ziegler, Alfred Wittinghofer, and Herbert Waldmann*
Abstract: N-Terminal myristoylation facilitates membrane
binding and activity of proteins, in particular of Src family
kinases, but the underlying mechanisms are only beginning to
be understood. The chaperones UNC119A/B regulate the
cellular distribution and signaling of N-myristoylated proteins.
Selective small-molecule modulators of the UNC119–cargo
interaction would be invaluable tools, but have not been
reported yet. We herein report the development of the first
UNC119–cargo interaction inhibitor, squarunkin A. Squarun-
kin A selectively inhibits the binding of a myristoylated peptide
representing the N-terminus of Src kinase to UNC119A with an
IC50 value of 10 nm. It binds to UNC119 proteins in cell lysate
and interferes with the activation of Src kinase. Our results
demonstrate that small-molecule inhibition of the UNC119–
cargo interaction might provide new opportunities for modu-
lating the activity of Src kinases that are independent of direct
inhibition of the enzymatic kinase activity.
N-Terminal protein myristoylation facilitates the reversi-
ble binding of proteins to membranes,[7] but the mechanisms
dictating selective subcellular localization are only beginning
to be understood. In an analogous system concerning the
localization of lipidated proteins, the intermembrane shut-
tling, subcellular localization, and activity of C-terminally
S-farnesylated proteins such as the Ras and Rheb GTP-
binding proteins are mediated by the PDE6d chaperone,
which binds the lipidated C-terminus.[8] Small-molecule
inhibitors of the PDE6d–Ras and PDE6d–Rheb interactions
have proven to be invaluable tools in the unraveling of the
corresponding mechanisms.[9] Moreover, the inhibition of
these interactions with small molecules impairs the local-
ization and oncogenic signaling of Ras and Rheb proteins.[10]
By analogy, selective inhibitors of the interactions between
UNC119 chaperones and their N-myristoylated cargo might
be powerful tools for uncovering the biological mechanisms
guiding the subcellular localization of the cargo proteins and
might open up novel opportunities to interfere with their
activity. This could be particularly relevant for the Src kinase.
Src is involved in many critical processes such as cell growth,
proliferation, angiogenesis, and survival.[11] Uncontrolled
overexpression and overactivation of Src is observed in
various cancer types,[12] and kinase inhibitors targeting the
ATP-binding site of Src are in high demand.[13] However,
owing to the high sequence and structural homology of kinase
ATP-binding sites, such inhibitors need to be highly selective,
which complicates their development.[14] Therefore, novel
approaches to modulate kinase activity by alternative strat-
egies are needed.[15]
T
he UNC119A and UNC119B proteins are homologous
molecular chaperones that specifically bind the lipidated
N-termini of N-myristoylated proteins and modulate their
cellular shuttling, subcellular localization, and activity.[1]
UNC119 cargo includes ciliary proteins such as nephrocys-
tin-3[2] and N-acylated G protein a-subunits,[3] and UNC119
was linked to the trafficking and activation of the
N-myristoylated Src family tyrosine kinases Lck, Lyn, and
Fyn.[4] In particular, Bastiaens[5] and co-workers very recently
demonstrated that UNC119 also regulates the subcellular
localization and activity of the Src kinase itself, a major
oncogene and target in anticancer drug discovery.[6]
Analysis of the crystal structure of UNC119A in complex
with a myristoylated peptide[3c] using DogSite Scorer[16] to
predict druggability suggests that the lipid-binding pocket of
UNC119 should be amenable to targeting with small mole-
cules (Figure 1). However, small-molecule inhibitors blocking
the interaction of UNC119 with its cargo have not been
identified yet.
[*] Dr. T. Mejuch, G. Garivet, W. Hofer, N. Kaiser, Dr. S. Ziegler,
Prof. Dr. H. Waldmann
Department of Chemical Biology
Max-Planck-Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
Herein, we report the development of the first small-
molecule ligand of the UNC119 lipid-binding site, named
squarunkin A. Squarunkin A inhibits the binding to
UNC119A of a myristoylated peptide representing the
N-terminus of Src with an IC50 value of 10 nm and does not
target the lipoprotein-binding sites of other lipoprotein
chaperones, such as PDE6d, AIPL1, and RhoGDI, which
bind S-prenylated proteins. The compound binds to UNC119
in cell lysate and interferes with Src activation.
Dr. T. Mejuch, G. Garivet, W. Hofer, N. Kaiser, C. Ehrt, Dr. O. Koch,
Prof. Dr. H. Waldmann
Faculty of Chemistry and Chemical Biology
TU Dortmund University
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Dr. E. K. Fansa, Prof. Dr. A. Wittinghofer
Department of Structural Biology
Max-Planck-Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Dr. M. Baumann
To identify small-molecule ligands for the UNC119 lipid
binding site, we employed a screening assay based on the
homogeneous time resolved fluorescence (HTRF) tech-
nique.[17] In the assay, GST-tagged UNC119A protein
together with an anti-GST antibody fused to a Eu3+ cryptate
Lead Discovery Center GmbH
Otto-Hahn-Strasse 15, 44227 Dortmund (Germany)
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.201701905.
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Figure 1. A) Structure of the lipid-binding protein UNC119A (green) in complex with a myristoylated NPHP3 peptide (orange sticks, PDB:
5L7K).[3c] B) The UNC119A cavity can potentially accommodate small-molecule inhibitors.
complex was used as the FRET donor. A myristoylated and
biotinylated N-terminal peptide derived from the Src protein
that binds to UNC119A with a KD of 91 nm[18] and strepta-
vidin-d2 complex served as the FRET acceptor. In the
presence of an inhibitor, the complex between the donor
and the acceptor is destabilized, and the emission signal from
the acceptor is abolished (for an illustration of the assay
principle, see Figure S1 in the Supporting Information).
Initially, our in-house compound library (ca. 200000
members) was screened to identify compounds that reduced
the signal to less than 50% at 1.25 mm concentration. For the
500 most potent compounds, IC50 values were determined by
means of the HTRF assay. Several of the most potent
compounds were based on a squaramide scaffold.
Variation of the squaramide substituents (Table 1; for
details, see Table S1) revealed that for activity, one substitu-
ent should be a 4-amino-substituted piperidine carrying
a carbamate group. Compounds with piperazine, morpholine,
or phenyl moieties instead of the 4-aminopiperidine were
inactive. Moreover, whereas the N-ethoxycarbonyl-substi-
tuted inhibitor 3a is very potent, the shorter N-acetyl
analogue, the non-acylated aminopiperidine, and the
4-aminopyridine derivative do not inhibit the interaction
(3b–3d). For the second amide substituent, the best inhibitors
contained a 4-aryl-substituted piperazine attached to the
squaramide core via a short alkyl linker. Replacement of the
aryl group by a benzyl or alkyl group resulted in reduced or no
inhibitory activity (Table S1). For the linker, two or three
methylene groups are best (3a, 3 f, and 3g), and in the absence
of a linker, the activity is lost (3e). Substitution in the meta
position of the aromatic ring yielded compounds that are
more active than the corresponding ortho- or para-substituted
analogues (3a, 3h, and 3i). The best results were obtained
with Cl- and CF3-substituted arenes (3a, 3 f, 3j, and 3k).
Several compounds displayed low nanomolar IC50 values (3a,
3 f, 3j, and 3k). To prioritize the hits, we determined their
kinetic solubility and investigated them in parallel artificial
membrane assay (PAMPA) experiments (Table 1). The data
revealed that the hits have comparable kinetic solubility
(except for 3 f, which has significantly higher solubility). For
compounds 3a and 3j, comparable membrane permeability
was measured that was significantly higher than the perme-
ability recorded for 3 f and 3k. In light of these data,
compound 3j (“squarunkin A”) was chosen for further
evaluation as it offers the best compromise between low
nanomolar activity, good membrane permeability, and suffi-
cient kinetic solubility.
All attempts to crystallize UNC119 in complex with an
inhibitor met with failure. Therefore, an exhaustive in silico
analysis including docking and molecular dynamics (MD)
simulations was performed to gain insight into the putative
binding mode of the compounds. A visual inspection of the
obtained docking-based binding modes led to a hypothetic
common binding mode for nearly all compounds that is in
accordance with the structure–activity relationship (see Fig-
ure 2A for the binding of squarunkin A). Owing to the size of
the binding pocket and the high number of possible inter-
actions, MD simulations were performed to strengthen this
binding hypothesis. The simulation confirmed the proposed
binding mode, and during the simulations, two hydrogen
bonds between Glu163 as a hydrogen-bond acceptor and the
two nitrogen atoms bordering the C2 alkyl linker in the
molecule were identified as the most prominent interactions
(Figure 2B).
Based on this binding mode, squarunkin A appears to give
rise to p–p stacking interactions of the phenyl moiety with
Phe196, hydrogen bonds to Asn230 and Tyr234, and addi-
tional hydrogen bonds to Glu163 and Ser218. The trifluoro-
methyl-substituted aryl ring is located in a hydrophobic
pocket formed by Tyr236, Leu199, Leu138, Met207, and
Phe196 (Figure 2A). During the MD simulations, the aryl
substituent rearranges in an adjacent hydrophobic subpocket
formed by aromatic (Phe196, Tyr194, Phe91) and aliphatic
residues (Ile93, Val143; Figure 2B). The ethyl group of the
ester substituent occupies a hydrophobic region lined by
Ile105 and Val129. The latter hydrophobic contacts seem to
be important for binding as compounds 3b and 3c, which lack
the ethyl group, show no binding compared to squarunkin A
(Figure S2).
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Table 1: Synthesis and evaluation of squaramide-based inhibitors of the interaction between UNC119A and myristoylated cargo.[a]
Compound
R1
R2
IC50
[nm]
Kinetic solubility
[mm]
PAMPA
[% flux]
3a
3b
14Æ1
20.1
n.d.
51.3
n.d.
inactive
3c
3d
inactive
inactive
n.d.
n.d.
n.d.
n.d.
3e
3 f
3g
3h
3i
inactive
7Æ1
n.d.
269.2
n.d.
n.d.
22.5
n.d.
n.d.
n.d.
48.4
30.9
31Æ4
91Æ10
25Æ1
10Æ1
8Æ1
n.d.
n.d.
3j
19.5
23.0
3k
[a] All data are shown as mean Æ SD of three independent experiments. n.d.=not determined.
To determine the selectivity for binding to the UNC119A
protein, squarunkin A was tested for the inhibition of cargo
binding by other lipid-binding proteins, in particular the
farnesyl-binding proteins PDE6d,[19] AIPL1,[20] and calmodu-
lin[21] and the geranylgeranyl-binding protein RhoGDI[22]
(Figure 3). To this end, binding of fluorescently labeled
myristoylated Src,[18] farnesylated Rheb,[23] and geranylgera-
nylated Rab1[18] peptides to the corresponding lipid-binding
protein was monitored in fluorescence polarization assays.
The assays revealed that only the binding of the Src peptide to
UNC119A was outcompeted by squarunkin A.
For proof of target engagement by squarunkin A in
a complex cellular environment, a cellular thermal shift
assay (CETSA) experiment in Jurkat cell lysate using tandem
MS/MS analysis readout was performed. In this experiment,
the thermal stabilization of the UNC119 proteins upon
binding to the ligand was determined (Figure 4A). Squar-
unkin A stabilizes both isoforms UNC119A and UNC119B
with thermal shifts of 6.168C and 8.078C, respectively.
To determine the activity of squarunkin A in cells, its
influence on the activation of Src was monitored. Myristoy-
lation and membrane localization of Src are critical for its
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Figure 2. A) Docking- and B) molecular-dynamics-based putative binding modes of compound 3j to UNC119A. The compound (orange, ball-and-
stick representation) mainly interacts with the protein via various hydrogen bonds (green springs) while the aryl moiety occupies the hydrophobic
pocket at the bottom of the binding site.
Figure 3. A) Structure of squarunkin A. B) Determination of the selective binding of squarunkin A to UNC119A compared to the lipid-binding
proteins PDE6d, AIPL1, calmodulin, and RhoGDI, as determined by means of fluorescence polarization measurements. The concentrations of the
components are indicated.
kinase activity.[24] Inactive Src is phosphorylated at the
regulatory tyrosine Y527 while phosphorylation of tyrosine
Y416 is required for activity. Upon membrane localization,
Y527 is dephosphorylated, resulting in a conformational
change of Src, and Y416 is phosphorylated, yielding active Src
kinase. The impact of inhibiting the UNC119–Src interaction
on changes in Y416 phosphorylation of Src (and thereby its
activation) was monitored by means of an in-cell Western
assay[25] in the triple-negative breast cancer cell line MDA-
MB-231, which expresses high levels of Src. Treatment of the
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Figure 4. Biochemical evaluation of squarunkin A. A) Cellular thermal shift assay of UNC119 proteins upon treatment with DMSO control (red)
and squarunkin A (blue). Lysates from Jurkat cells were treated with squarunkin A at 1 mm concentration, and thermal stabilization of the proteins
was identified and quantified by means of tandem MS/MS analysis. B) Squarunkin A inhibits the phosphorylation of Y416 in Src. MDA-MB-231
cells were treated with various concentrations of squarunkin A (2.5, 0.625, 0.078, and 0.01 mm) or DMSO and dasatinib (0.078 mm) as controls.
Phosphorylation of Src Y416 was detected and quantified by means of an in-cell Western assay. Data are presented as mean values Æ SD (N=4,
n=3) and were normalized to the amount of total Src; ns=non-significant, ** p<0.01, *** p<0.001 as determined by an unpaired, two-tailed
Student’s t-test.
cells with increasing concentrations of squarunkin A led to
a concentration-dependent reduction of Src phosphorylation
(Figure 4B). A significant decrease in phosphorylation level
was observed already upon treatment with 0.078 mm of
squarunkin A. At a concentration of 0.625 mm, the phosphor-
ylation of Src (Y416) was reduced to 40%. At these
concentrations and up to 10 mm, squarunkin A is non-toxic
to cells and does not induce apoptosis (Figures S3 and S4).
Similar results were obtained by immunoblotting (Figure S5).
In conclusion, we have developed squarunkin A as the
first specific small-molecule inhibitor of the interaction
between UNC119 proteins and myristoylated cargo. Molec-
ular modeling studies suggest that squarunkin A interacts
with the hydrophobic pocket of the UNC119 proteins and
potently competes with lipidated cargo for binding. Squar-
unkin A binds to UNC119 in cell lysate and interferes with
the activation of Src kinase. While mechanistic conclusions
cannot be drawn from our experiments, the results demon-
strate the potential of squarunkin A as a novel compound to
investigate the biology of the UNC119 proteins and their
myristoylated cargo proteins.
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Acknowledgements
This research was supported by the Deutsche Forschungsge-
meinschaft (Sonderforschungsbereich SFB 642 to A.W. and
H.W.). T.M. acknowledges the Alexander von Humboldt
Foundation for a Research Scholarship. C.E. is funded by
a Kekulꢀ Mobility Fellowship from the Chemical Industry
Fund (FCI). O.K. thanks the German Federal Ministry for
Education and Research (BMBF, Medizinische Chemie in
Dortmund, Grant BMBF 1316053) for funding. We thank
Christine Nowak for the cloning and expression of UNC119
protein and Dr. Petra Janning, Dr. Marc Schꢁrmann, Jens
Warmers, and Malte Metz for assistance with the establish-
ment and analysis of CETSA experiments.
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Keywords: chemical biology · medicinal chemistry · Src kinase ·
structure–activity relationships · UNC119 protein
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Manuscript received: February 21, 2017
Revised: March 30, 2017
Final Article published: && &&, &&&&
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Communications
Medicinal Chemistry
Cargo unloading: The first specific small-
molecule inhibitor of the interaction
between UNC119 proteins and myristoy-
lated cargo, squarunkin A, was devel-
oped. Squarunkin A interacts with the
hydrophobic pocket of the UNC119 pro-
teins and interferes with the activation of
Src kinases.
T. Mejuch, G. Garivet, W. Hofer, N. Kaiser,
E. K. Fansa, C. Ehrt, O. Koch,
M. Baumann, S. Ziegler, A. Wittinghofer,
H. Waldmann*
&&&& — &&&&
Small-Molecule Inhibition of the
UNC119–Cargo Interaction
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