Development of Kinase Inactive PD173955 Analogues for Reducing Production of Aβ Peptides

Article abstract of DOI:10.1021/acsmedchemlett.9b00213

Compound 3a, DV2-103, is a kinase inactive analogue of a potent Abl1/Src kinase inhibitor, PD173955, 2. Both compounds, 2 and 3a, are known to reduce production of beta amyloid (Aβ) peptide in cells and animal models. We have now prepared and evaluated a

Full text of DOI:10.1021/acsmedchemlett.9b00213

Letter
pubs.acs.org/acsmedchemlett
Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
Development of Kinase Inactive PD173955 Analogues for Reducing
Production of Aβ Peptides
Anjana Sinha, Katherina Gindinova, Emily Mui, William J. Netzer, and Subhash C. Sinha*
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10065, United States
S
* Supporting Information
ABSTRACT: Compound 3a, DV2-103, is a kinase inactive
analogue of a potent Abl1/Src kinase inhibitor, PD173955, 2.
Both compounds, 2 and 3a, are known to reduce production
of beta amyloid (Aβ) peptide in cells and animal models. We
have now prepared and evaluated a series of PD-173955
analogues, several of which reduced Aβ production potently.
This occurs in cells expressing human full-length amyloid
precursor protein (APP) and not in cells expressing APP β-C
terminal fragment (APP-C99), suggesting that the kinase
inactive analogues strongly affect β-secretase (BACE1)
cleavage of APP, similarly to Gleevec. A combination of the kinase inactive analogues of PD173955 with a BACE1 inhibitor
(BACEi), namely, BACE IV, strongly reduced Aβ levels in cells, as noted previously with Gleevec and analogues. Several potent
compounds also penetrated and accumulated in mouse brain in high nanomolar to low micromolar concentration.
KEYWORDS: Alzheimer’s disease, Aβ peptide, β-secretase, DV2-103, PD173955
wo potent Abl and Abl/Src kinase inhibitors, imatinib
including 3m, 5b, 5c, and 5f (Figure 1), showing that these
compounds reduce production of both Aβ40 and Aβ42 at low
micromolar concentrations. Moreover, compound 3a ana-
logues strongly enhance the Aβ-lowering effect of BACE IV, a
1
2
T(Gleevec), 1, and PD-173955, 2, respectively, and a
kinase inactive analogue of 2, i.e., 3a (DV2-103),3 were
previously shown to potently reduce production of secreted β-
amyloid (Aβ) peptide in cells.4,5 Compounds 1, 2, and 3a also
reduced Aβ levels in guinea pigs4 or in mice5 that express three
Alzheimer’s disease (AD)-related mutations.6 Aβ40 and Aβ42
peptides are two major isoforms of Aβ peptides found in AD
brain.7 These peptides accumulate in AD brain in the form of
amyloid plaques when levels of both isoforms as well as the
Aβ42/Aβ40 ratio rise.8 Production of Aβ peptides from the
amyloid precursor protein (APP), which is an integral
membrane protein expressed abundantly in neurons,9 is
mediated by β-secretase (BACE1) and γ-secretase (GS)
proteases.10,11 However, a general inhibition of these proteases
using their inhibitors, BACEi or GSi,12,13 have failed in clinical
trials for the treatment of Alzheimer’s disease (AD).14−16
These inhibitors cause deleterious side-effects by inhibiting
cleavage of other protein substrates, such as Neuregulin and
Notch1.17,18 In contrast, compounds 1 and 3a5 indirectly
inhibited BACE1 cleavage of APP19 and did not affect
processing of other BACE1 substrates tested.5 Additionally, a
combination of compound 1 with a BACEi strongly reduced
Aβ production in cells with a potency that is greater than the
additive effects of each inhibitor.5,20 Now, we are developing 1
and 3a analogues for use as single agents, and in combination
with a BACEi. When combined with a BACEi, the 1 and 3a
analogues could reduce production of both Aβ40 and Aβ42
peptides, and enhance the efficacy of a BACEi while
minimizing its associated side effects.21 Described in this
communication are syntheses and evaluations of 3a analogues,
Figure 1. Structure of Abl or Abl/Src kinase inhibitors, Gleevec
(Imatinib), and PD-173955, and the representative kinase inactive
compound 3a (DV2-103) and PD-173955 analogues.
Received: May 11, 2019
Accepted: August 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.9b00213
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Figure 2. Synthesis of PD-173955 analogues: (A) 3b−p, 4a−m, and 5a−f, and (B) 5g−n. aCompounds 3l, 4e, 4k, and 5e are HCl salts, prepared
by treating the Boc-protected coupled products with 4 M HCl in dioxane and EtOAc.
potent BACEi, in a nonadditive manner (analogue + BACEi).
This finding is consistent with our prior reports where 1 and
BACE IV combinations were used,5,20 and provides further
rationale behind our ongoing efforts to develop and identify
potent, selective and effective combination.20
Chemistry. We designed and prepared a series of 3a
analogues, including compounds 3b−p, 4a−m, and 5a−n
(Figures 1 and 2). Unlike compound 2 and the previously
described analogues of compound 2, which were shown to
inhibit γ-secretase cleavage of APP without affecting Notch
cleavage,22 all 3a analogues lack NH ‘H’ attached to pyrimidine
(shown by an asterisk (*) in compound 2 in Figure 1).
Because the crystal structure of the kinase domain of c-Abl
kinase complexed with compound 2 has shown that the latter
makes an important contact through “NH” attached to the
pyrimidine ring with Met318 of the kinase,23 the 3a analogues
B
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Figure 3. PD-173955 analogues reduce Aβ production potently by affecting BACE1 cleavage of APP and do not inhibit Abl and Src kinases. (A)
Compound 3a, 3m, 5b, 5c, and 5f reduced production of Aβ40 and Aβ42 peptides from N2a695 cells. Aβ40 and Aβ42 levels in cell supernatants
post treatment with compounds were measured using human Aβ ELISA kits. (B) Compounds 3m, 5b, 5c and 5f did not inhibit or weakly inhibited
Abl and Src kinase activity at 10 μM compound concentration (kinase activity assays were performed by Luceome Biotechnologies, Tucson,
Arizona). Compound 3a is known to not inhibit Abl and Src kinase (ref 5). (C, D) Effects of 3a analogues on Aβ production in N2a cells
transfected with human (C) APP-FL or (D) APP-C99, measured by ELISA. DAPT is used as a positive control, and MK8931 is used as positive
control in (C) and a negative control in (D). All experiments were performed in duplicate, and results shown here are the representative of two
independent experiments. Statistical significance: *P < 0.05%; **P < 0.01%.
were expected to bind c-Abl kinase less efficiently. Thus, we
anticipated that the effects mediated by these compounds on
Aβ production could be considered independent of Abl kinase
inhibition as was shown previously for 3a.5 We prepared
compounds 3b−p, 4a−m, and 5a−h using the readily available
intermediates 6a−c and 8a (Figure 2). Compounds 6a24 and
8a25 were obtained as described,22,24,25 and converted to the
sulfone derivatives 7a and 8b by reacting with m-CPBA.
Compounds 6b and 6c were prepared similarly22 by modifying
the synthesis of 6a and converted to 7b and 7c by reacting
with m-CPBA (see Supporting Information Scheme S-1).
Subsequently, compounds 7a−c were reacted with various
piperazine derivatives or with amines to afford 3b−p, 4a−m,
and 5a−f; and 8b was reacted with N-methylpiperazine to give
9. The latter underwent Suzuki−Miyaura coupling26 with
aryllboronic acids affording compounds 5g−n.
all experiments. Cell supernatants were collected and Aβ40
levels were measured using commercially available human
Aβ40 ELISA kits. We found nine compounds, including 3c, 3l,
3m, 4m, 5b−d, 5f, and 5l, were equally or more potent than 1
(Figure S-1). To confirm that the reduction in Aβ40
production by all nine compounds was not due to the toxicity,
we determined the toxicity of these compounds at 10 μM
concentration by incubating with N2a cells for 5 and 24 h and
determining the number of viable cells using the MTT assay.
We also used 3a (10 μM) and 2 (1 μM) for a comparison. We
found all compounds, except 3c and 5c, were nontoxic (Figure
S-2). Compounds 3c and 5c showed some toxicity in 24 h, but
not in 5 h. These results suggested that the toxicity of
compounds 3c and 5c did not contribute to their effects on Aβ
production in the 5 h assay.
For the sake of a preliminary structure−activity relationship
(SAR) among the nine active analogues of 3a, i.e., 3c, 3l, 3m,
4m, 5b−d, 5f, and 5l, we pooled these compounds into group
1 and 2 depending upon whether the compounds lack or
contain an additional (NHBoc or NHCOCMe3) substitution
in ring D. Based on the screening data and further evaluation
(see latter), we found that addition of NHBoc or NHCOCMe3
Evaluations. Initially, we screened all analogues to select
potent compounds by determining their effects on Aβ
production in N2a695 cells. The latter express sufficient
Aβ40 peptide in 5−6 h. For this, we incubated compounds at
10 μM with N2a695 cells for 6 h at 37 °C, as described
previously.5 Gleevec (10 μM) was used as a positive control in
C
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Figure 4. PD-173955 analogues reduce Aβ production potently in N2a695 cells preincubated with BACE IV. Two sets of experiments were
performed using cells treated with DMSO alone or BACE IV for 1 h, before treatment with the freshly prepared media containing compounds 3a,
5b, and 5f. Shown on the left are (A) Aβ40 and (B) Aβ42 levels measured using human Aβ ELISA kits as percent of DMSO control for both
experiments, and on the right are the BACE IV-pretreated experiment as percent of BACE IV-pretreated DMSO (depicted as *DMSO) control. All
experiments were performed in duplicate or triplicate, and the results shown here are average of three independent experiments. Statistical
significance: *P < 0.05%; **P < 0.01%; ***P < 0.001%.
substitution in ring D generally increased the activity compared
to the analogous compounds lacking one of these functions.
However, this also increased molecular weight (MW) of the
resulting products, as in 5b−d and 5f, and violated Lipinski’s
rules.27 We further calculated the ADME properties, including
gastrointestinal (GI) absorption, blood-brain barrier (BBB)
permeation, and P-gp interaction, and synthetic accessibility of
compounds 3c, 3l, 3m, 4m, 5b−d, 5f, and 5l, as compared to 2
and 3a using SwissADME (http://www.swissadme.ch/index.
php) web tool.28 The calculated values, as shown in Table S-2,
suggested that all these compounds could possess high GI
absorption and likely to be distributed in the body readily.
Second, group 1 compounds, including 3a, are likely to be BBB
permeant, whereas compound 2 and the group 2 compounds
are not. Third, all compounds, except 2 and the analogues 3a,
3m, 5d and 5l, were predicted as the P-gp substrates. Fourth,
all compounds possess synthetic accessibility score less than 5
(on 1 to 10 scale for easy to difficult synthesis).29 Thus, we
found compounds 3m and 5l suitable for further profiling
based on both the activity and physicochemical properties of
these compounds. We focused on compound 3m and
compared its activity with 5b, 5c and 5f. Compound 3m
possesses identical substitution in the piperazine “A” ring as in
5c and 5f, but lacks the NHBoc or NHCOCMe3 substitution
in the D ring, whereas both 5b and 5c possess NHBoc
substitution in the D ring and two different substitutions in the
piperazine “A” ring.
experiments. As shown in Figure 3A, all four compounds 3m,
5b, 5c, and 5f (10 μM) reduced Aβ40 and Aβ42 production
more potently than 3a (20 μM) did. Separately, to confirm
that 3a analogues reduce Aβ production through a pathway
not requiring the inhibition of Abl or Src kinase activities, we
examined the effects of these compounds on Abl and Src
kinase activity. The kinase assay was performed (by an
outsourcing company) with compounds set at a concentration
of 10 μM, as described.30 The results shown in Figure 3B
clearly reveal that compounds 3m, 5b, 5c, and 5f do not inhibit
Abl or Src kinases potently, while these compounds reduce Aβ
production by >50% in cellular assays. These data indicate that
3a analogues 5b, 5c and 5f reduce Aβ production independent
of Abl and Src kinase and in that regard are similar to 1 and
3a.5
The amyloidogenic BACE1 cleavage of APP yielding soluble
APPβ (sAPPβ) and the membrane bound β-C terminal
fragment (βCTF) compete with a parallel nonamyloidogenic,
α-secretase cleavage process that produces soluble APPα
(sAPPα) and the APP α-C terminal fragment (αCTF). Here,
α-secretase cleaves APP within the Aβ region, thus preventing
amyloidogenic processing by BACE1.31 Compound 2 was
earlier shown to reduce Aβ production by inhibiting the
subsequent γ-secretase cleavage of βCTF.4 However, we have
recently shown that 1 and compound 3a reduce production of
Aβ primarily through shifting the β-cleavage to a non-
amyloidogenic cleavage.5 Treatment with these compounds
produced multiple long CTFs, including a 16 kDa CTF
consisting of the C-terminal 141 amino acids of APP (CTF-
141) which may have been produced by lysosomes, where it
was most abundant.5 To examine whether compound 3a
We confirmed the activity of compounds 3m, 5b, 5c, and 5f
by determining their effects on production of both Aβ40 and
Aβ42. Compound 3a was used at 20 μM, and compounds 3m,
5b, 5c, and 5f were tested at 10 μM concentrations in these
D
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analogues also affect APP cleavage through either or both
BACE1 and γ-secretase cleavage of APP, we examined their
effects on production of Aβ peptides in N2a cells transfected
with human APP-FL (full length) or with APP-C99 (βCTF),
as described previously for Gleevec and analogues.20 We used
3a and analogues at 10 μM concentration. We also used
BACEi MK8931 (0.5 μM) and GSi DAPT (1 μM) as controls.
The results are shown in Figure 3C, D and SI Figure S-3. We
found that the analogues of 3a, including compounds 5b and
5f, reduce production of both Aβ40 and Aβ42 peptides in
APP-FL cells, but only of Aβ42 peptides in APP-C99 cells.
None of the 3a analogues reduced Aβ40 peptides in APP-C99
cells. These results suggest that compounds 5b and 5f
modulate BACE1 cleavage of APP, and in that respect are
similar to Gleevec and 3a.5
The kinase inactive analogues of PD173955 can be combined
with a BACEi to further reduce production of Aβ peptides.
Additional modifications of 3a analogues, especially in rings B
and C, and identification of compounds mediating a synergistic
effect when combined with a BACEi remain the subject of
future studies. We also plan to assess the effects of long CTFs
(e.g., C141) and other APP fragments on cellular viability.
EXPERIMENTAL PROCEDURES
Synthesis and characterization as well as screening and evaluation of
PD-173955 analogues are described in the Supporting Information.
■
Statistical Analysis. The data are presented as means
SEM.
Data were analyzed by Student’s t test for single comparison and one-
way ANOVA for multiple comparisons, and those showing P value <
0.05 were considered significant.
Earlier, we showed that a combination of BACE IV and 1 or
its analogues reduce Aβ peptide secretion more potently than
the sum of inhibitions produced by BACEIV and 1 used alone
at equivalent concentrations.5,20 By using a combination of 3a
or analogues and a general BACEi, we hope to reduce an
effective dose, and thereby the toxicity, of the latter. This led us
to further examine a combination of the PD-173955
analogues/BACE-1 inhibitor, BACE IV, and determine
whether one of the potent PD-173955 analogues could also
mediate a synergistic effect. We performed experiments by
preincubating N2a695 cells with DMSO or 0.5 μM BACE IV
alone for 1 h before further incubating with fresh media
containing 5 μM compound 3a (or its analogues 5b or 5f)
only. Indeed, we found that the 3a analogues 5b or 5f reduced
both Aβ40 and Aβ42 production significantly compared to
BACE IV-pretreated DMSO control alone (Figure 4A,B). This
study has prompted us to develop and perform a larger
screening study, in which brain-permeable 1 and 3a analogues
and BACEi’s can be evaluated in combination.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.9b00213.
■
S
General synthetic procedures, and characterization of
synthesized compounds including 1H NMR spectra and
MS data. Figures showing screening data of all synthetic
analogues and evaluation of selected compounds (PDF)
SMILES data for compounds 3a−p, 4a−m, and 5a−n
(XLSX)
AUTHOR INFORMATION
Corresponding Author
*E-mail: ssinha@rockefeller.edu. Phone: 212-327-8121.
ORCID
■
Subhash C. Sinha: 0000-0001-8916-5677
In the current study, we have developed and evaluated
kinase inactive analogues of 2 that possess B and C rings
identical to 3a3,5 and the parent compound 2, and there has
been greater emphasis on A and D rings (Figure 1). While it
would be interesting to also perform modifications of B/C
rings and determine the impacts of such changes on drug
activity, we have already identified 3a analogues, including 3m,
5b, 5c, 5f, or 5l, which can be further modified and used,
especially in combination with a BACEi for reducing Aβ levels.
Because Aβ peptides start accumulating in AD brain years
before the onset of dementia,32 we anticipate that such
compounds and combinations could be developed best for AD
prevention. In a follow up study, we will develop and evaluate
3a analogues as single agents as well as in combination with a
BACEi to determine their effects in an AD prevention model.
Conclusion. Kinase inactive analogues of PD173955,
including compounds 3m, 5b, 5c and 5f, were developed as
potent inhibitors of Aβ peptide production. These compounds
function mainly through modulating the BACE1 cleavage of
APP. The potential action mechanism of compounds 1 and 3a
were discussed in an earlier study,5 which suggested that the
compounds alter trafficking of APP away from recycling
endosomes (where most Aβ is formed) to lysosomes where
APP is degraded, thus bypassing the cell’s primary Abeta
producing (amyloidogenic) pathway. The effects of the
PD173955 derivatives on APP metabolism, especially those
of 3a, are essentially identical to the effects of 1 and 3a on APP
metabolism. Therefore, we believe that the mechanism of
action of the derivatives is the same as that noted for 1 and 3a.
Author Contributions
A.S., W.J.N., and S.C.S. designed the experiments, A.S., K.G.,
E.M., W.J.N., and S.C.S. performed the experiments, and A.S.,
W.J.N., and S.C.S. wrote the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to Drs. Sagi Vasudenva Naidu and Saumya
Roy for conducting preliminary studies at the Scripps Research
Institute, La Jolla, CA and to Ms. Mondana Ghias and Emily
Chang for performing ELISA assays of some compounds. We
are also thankful to Dr. Victor Bustos of the Rockefeller
University for helpful discussions and to the Rockefeller
Screening and Proteomics centers and Memorial Sloan
Kettering Spectroscopic center for the 1H NMR and MS
spectral data of the compounds. Funding support from JPB
foundation (Grant #322 and 839) is duly acknowledged.
ABBREVIATIONS
■
Aβ, beta amyloid, amyloid beta; Abl, Abelson murine leukemia
viral oncogene homologue 1; AD, Alzheimer’s disease; APP,
amyloid precursor protein; BACE1, β-secretase; BACEi, β-
secretase inhibitor; CTF, carboxy terminal fragment; ELISA,
enzyme-linked immunosorbent assay; FL, full length; GS, γ-
secretase or gamma secretase; GSi, γ-secretase inhibitor;
mCPBA, m-chloroperbenzoic acid; MS, mass spectrometry;
MSD, Meso Scale Discovery; Pd(PPh3)4, Tetrakistriphenyl-
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phosphine palladium(II); PTLC, preparative thin-layer chro-
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