Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy

Article abstract of DOI:10.1021/acsmedchemlett.9b00382

Herein, we report the discovery of a potent and selective dual DDR1/2 inhibitor, 7e (VU6015929), displaying low cytotoxicity, good kinome selectivity, and possessing an acceptable in vitro DMPK profile with good rodent in vivo pharmacokinetics. VU6015929

Full text of DOI:10.1021/acsmedchemlett.9b00382

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Letter
Discovery of VU6015929: A selective discoidin domain receptor 1/2
(DDR1/2) inhibitor to explore the role of DDR1 in anti-fibrotic therapy
Daniel E. Jeffries, Corina M Borza, Anna L. Blobaum, Ambra Pozzi, and Craig W Lindsley
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00382 • Publication Date (Web): 25 Nov 2019
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Discovery of VU6015929: A selective discoidin domain receptor 1/2
(DDR1/2) inhibitor to explore the role of DDR1 in anti-fibrotic therapy
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π
,║
†, ,║
ɸ
Daniel E. Jeffries,†,π Corina M. Borza, Anna L. Blobaum, Ambra Pozzi, * and Craig W. Lindsley
*
ψ,
ɸ
ψ, ϒ
†Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States
ɸDepartment of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States
║Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, United States
ψDepartment of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, USA
ϒVeterans Affairs Medical Center, Nashville, Nashville, TN 37232, USA
πThese authors contributed equally
KEYWORDS: discoidin domain receptor 1 (DDR1), tyrosine receptor kinase, collagen, fibrosis
ABSTRACT: Herein, we report the discovery of a potent and selective dual DDR1/2 inhibitor, 7e (VU6015929), displaying low
cytotoxicity, good kinome selectivity, and possessing an acceptable in vitro DMPK profile with good rodent in vivo pharmacokinetics.
VU6015929 potently blocks collagen-induced DDR1 activation and collagen-IV production, suggesting DDR1 inhibition as an
exciting target for anti-fibrotic therapy.
Receptor tyrosine kinases (RTKs) are a large family of cell-
surface receptors responsible for regulating cellular
proliferation, differentiation, survival, metabolism, and life
cycle.1 RTKs are divided into 20 subfamilies sorted by
structural similarity and associated endogenous ligand.
Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are
RTKs which, unlike other members of the receptor family, are
activated by collagens as opposed to peptide-like growth
factors.2 DDRs are widely expressed in developing organs,
while their expression in adult organs is low or undetectable.
DDR1 expression is predominant in epithelial cells; while
DDR2 is most commonly found in cells of mesenchymal
origin.3-6 Upon ligand binding these receptors can control
various cell functions including cell adhesion, migration,
survival and collagen production. Both receptors are well
documented to play critical roles during embryonic
development of mice and humans however their role during
adulthood is limited.3 Expression of DDR1 is low in regions of
the adult kidney such as the glomerulus; however its expression
can increase following glomerular injury.4 Upregulation of
DDR1 has been observed in patients with common kidney
diseases such as lupus nephritis and Goodpasture’s syndrome.
Genetic mouse models of chronic kidney disease show that
deletion of DDR1 improves survival and reduces fibrosis and
inflammation.5 In addition to DDR1’s pro-inflammatory effect
this receptor has also been implicated as having a deleterious
role in kidney injury via regulation of extracellular matrix
production by resident cells.6
Inhibitor 1 was originally reported as a selective DDR2
antagonist (IC50 = 18.6 nM), although it displayed similar
inhibition of DDR1 (IC50 = 12.4 nM).7 Efforts to identify DDR1
selective antagonists have yielded compounds such as 2
(DDR1-IN-1)8 with approximately four-fold selectivity for
DDR1 versus DDR2 and 3 with approximately twenty-fold
selectivity.9 Allosteric (type II/III) inhibitors, i.e. 4, of
DDR1/DDR2 have also been reported,10 but the recent Roche
compound 5 is the most selective to date for
H
N
N
O
O
H
H2N
N
CF3
O
N
H
N
N
N
H
O
O
CF3
O
2
1
N
O
N
N
H
N
N
N
N
N
N
S
N
N
N
H
H
O
N
CF3
3
4
O
Br
N
N
N
CF3
H
N
HN
O
O
5
Figure 1. Structures of reported compounds 1-5 that display inhibitory
activity against DDR1.
Blocking DDR1 activity with a small molecule inhibitor has
emerged as an attractive option to treat DDR1 related
progressions of fibrotic disease.2,6 Several small molecule
DDR1 antagonists have been reported to date (Figure 1).
DDR1 (~63-fold selective, but with a MW of 565).11,12 While
these ligands have garnered interest in DDR1 as an anti-fibrotic
therapeutic agents, either cytotoxicity, kinome selectivity,
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broader selectivity or poor DMPK profiles (or a combination of methyl-3-nitrobenzoic acid or 4-fluoro-3-nitrobenzoic acid 8
1
2
3
4
5
6
7
8
all four) have precluded more definitive proof of concept
underwent a HATU-mediated amide coupling with 3- or 3,4-
disubstituted anilines 9 to afford, after a microwave-assisted
nitro reduction with SnCl2, anilino amides 10 in yields ranging
from 32-96% for the two steps. Treatment of anilino amides 10
with 5-bromonicotinaldehyde under reductive amination
conditions yields 11 in 43-77% isolated yields. Finally, a
standard Suzuki coupling reaction with 11 and various
heteroaryl boronic acids delivers analogs 7 in 38-63% yields.13
studies from being performed, and additional tools are needed.6-
12
While awaiting new high-throughput screening (HTS) hits,
we utilized 1, due to its clean ancillary kinome panel,7 and
showed that inhibition of DDR1 by 1 significantly reduced
DDR1-mediated collagen IV production;6 however, the DMPK
profile of 1 proved unacceptable along with noted cytotoxicity
at modest concentrations. Thus, we elected to perform a multi-
dimensional optimization campaign focused on 1, surveying a
broad range of chemical diversity (Figure 2).
Scheme 1. Synthesis of analogs 7.a
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H2N
R2
R3
R1
R1
a, b
c
H
+
OH
N
R2
R3
O2N
H2N
O
O
8
9
10
Alternate substituents &
positional screen
R1
R1
Alternate substituents &
positional screen
H
H
Br
N
R2
R3
Het
N
R2
R3
d
N
N
H
H
N
O
O
N
N
H
H2N
N
CF3
11
7
N
H
O
O
aReagents and conditions: (a) HATU, N,N-diisopropylethylamine, DCM,
R
1
Linker homologation &
heteroatom screen
r.t., 17 hr, 49-91%; (b) SnCl2, EtOAc/EtOH, 110 oC (µW), 25 min, 67-95%;
Amide isoteres &
replacements
Additional substituents
o
(c) 5-bromonicotinaldehyde, NaBH3CN, AcOH, MeOH, 50 C, 2 hr, 43-
77%; (d) Aryl-B(OH)2, Pd(dppf)Cl2, Cs2CO3, 1,4-dioxanes / H2O, 90 oC, 3
Figure 2. Multi-dimensional optimization strategy for 1, exploring a wide-
hr, 38-63%.
range of structural diversity and assessing the minimum pharmacophore.
In short order, ~200 analogs were synthesized and screened
against both purified DDR1 and DDR2 kinase domains using a
LanthaScreen Eu kinase binding assay binding assay,6,13 and
~80% of these proved inactive, highlighting core elements of
the essential DDR1 pharmacophore (Figure 3). While
frustrating that SAR was steep, data derived from this initial
effort identified a smaller range of productive targets (7), and
focused subsequent efforts.
Table 1. Structures and DDR1/DDR2 activities of selected analogs 7.a
R1
H
Het
N
R2
R3
N
H
O
N
7
Cmpd
No.
Het
R1
R2
R3
DDR1 IC50
(nM)±SEM
DDR2 IC50
(nM)±SEM
O
7a
CH3
CH3
CF3
CF3
H
3.97±1.1
4.79±0.68
Et, i-Pr, t-Bu, OMe
substituent regioisomers
H2N
R1 = Me
N-Methylation
3-thiophene
4-isoxazole
7b
7c
Homologation to benzyl amide
H, Me, F, Cl, OCF3
H
15.2±2.3
11.0±1.5
R1
N
H
H
N
CF3
N
N
substituent regioisomers
H
H
O
N
R2
CH3
CH3
CF3
CF3
CH3
H
36.4±12
8.53±1.9
44.1±8.7
Imidazole
congeners
6
N
H
F, OMe
Oxo-linkage
Heterocycles,
cyclohexyl
Pyridyl regioisomers,
piperidine
N
N
N
7d
7e
4.56±0.61
N
F
OCF3
H
4.67±1.6
7.39±11.6
Het tolerated,
carboxamide
not
Me or F
essential
CF3 or OCF3
R1
essential
H
Het
N
R2
R3
7f
H
CH3
CH3
CF3
CF3
H
H
10.5±3.1
10.6±1.3
N
H
O
H or Me
N
7g
OCH3
5.89±2.02
6.36±0.77
7
aTR-FRET LanthaScreen Eu kinase binding assay with DDR1 and DDR2.6
homologation
tolerated
essential
The most robust series of active compounds are highlighted
in Table 1, and all active analogs were dual DDR1/DDR2
Figure 3. Regions and substituents explored in analogs 6 that were inactive
as DDR1/DDR2 antagonists (<30% tracer binding in presence of 100 nM
inhibitor, single point assay),6 leading to a basic DDR1 pharmacophore 7.
inhibitors.
We were pleased that a simple methylene
homologation afforded active compounds and our medicinal
chemistry strategy explored several avenues on further
The synthesis of analogs 7 (Scheme 1) required only four
steps from commercial starting materials. Here, either 4-
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improving compounds; here, one motivation was to find a
suitable isosteric replacement for the carboxamide moiety. The
1
2
3
4
5
6
7
8
matched-pair homologated analog of 1, the aminomethyl
pyridine 7a, proved more potent than the parent 1 (DDR1 IC50
= 3.97 nM, DDR2 IC50 = 4.79 nM). Replacement of the
carboxamide with a pyrrole as in 7b, was 4-to 5-fold less active
(DDR1 IC50 = 15.2 nM, DDR2 IC50 = 11.0 nM), and adding an
eastern 4-position substituent to 7b, to afford 7c, lost ~3-fold in
DDR inhibitory activity (DDR1 IC50 = 36.4 nM, DDR2 IC50
=
9
44.1 nM). Replacement of the pyrrole with a 3-N-
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methylpyrazole, such as 7d, showed improved activity (DDR1
IC50 = 8.53 nM, DDR2 IC50 = 4.56 nM), relative to 1. Within
the 7d core replacement of the methyl group in the central
phenyl ring with a fluorine, alongside substitution of the eastern
aryl methoxy to an aryl trifluoromethylether, provided another
Figure 4. Kinome selectivity and structure of 7e (VU6015929).
The high affinity binding of 6e to DDR1 kinase detected by the
LanthaScreen Eu kinase binding assay (Table 1) suggested that
7e would potently inhibit collagen-induced DDR1
phosphorylation in cells. To analyze the ability of 7e to inhibit
DDR1 phosphorylation in cells, we incubated serum-starved
HEK293 expressing full length human DDR1 cDNA (HEK293-
DDR1) with various amounts of lead compound 1 or 7e together
very potent analog 7e (DDR1 IC50 = 4.67 nM, DDR2 IC50
=
7.39 nM). Removal of the western heterocycle altogether, as
with the unsubstituted pyridine 7f, only lost ~2-fold (DDR1 IC50
= 10.5 nM, DDR2 IC50 = 10.6 nM). Finally, a simple OCH3
moiety, 7g, was also a viable heterocyclic/carboxamide
replacement (DDR1 IC50 = 5.89 nM, DDR2 IC50 = 6.36 nM).
As all analogs 6 were potent inhibitors of DDR1 and DDR2, we
employed a panel of in vitro DMPK assays to further triage
these compounds prior to deeper profiling. As a reference, the
lead 1 displayed low free fraction in plasma (rat fu = 0.018) and
high predicted hepatic clearance from liver microsomes (rat
CLhep = 60 mL/min/kg). Pyrrole-based 7b possessed an inferior
profile (rat fu = 0.001 and rat CLhep = 62 mL/min/kg), and thus
was precluded from further advancement, as were the majority
of analogs. Pyrazole 7d showed a comparable profile relative
to 1 profile (rat fu = 0.016 and rat CLhep = 46 mL/min/kg), while
7e was superior (rat fu = 0.089 and rat CLhep = 43.2 mL/min/kg)
as a potential rodent tool compound. Based on these data, 7e
was further evaluated in a rat IV (0.5 mg/kg)/PO (3 mg/kg) PK
study in a 10% EtOH/40% PEG400/50% saline vehicle
(solution). Here, 7e displayed a good in vitro:in vivo correlation
(IVIC), with moderate in vivo clearance (CLp = 34.2
mL/min/kg), an ~3 hour half-life, moderate volume of
distribution at steady state (Vss = 4.3 L/kg) and 12.5% oral
bioavailability with a rapid Tmax (0.75 hr). As 1 showed
cytotoxicity in mesangial cells expressing Hu-DDR1b at low
concentrations (~1 M) after a 24 hour incubation period, 7e
was assessed under similar conditions, and found to be without
cytotoxicity at 10 M. Finally, we evaluated the kinome
selectivity of 7e in a panel of 371 wild-type and mutant kinases
at a concentration of 1 M. Similar to the high selectivity
displayed by 1, 7e showed (Figure 4) potent inhibition of only
27/371 kinases (7.2%).11 Thus, based on the DDR1/DDR2
binding potency, the rat in vitro and in vivo DMPK profiles, a
lack of cytotoxicity and a favorably clean kinome profile, 7e
was advanced into key cell-based assays.
with
Figure 5. 7e blocks collagen I-induced DDR1 auto phosphorylation in
DDR1 expressing cells more potently than 1. (A) HEK293-DDR1b or (B)
HEK293-DDR1b-FLAG cells were treated with serial dilutions of 1 or 7e
then incubated with 50 µg/ml of collagen I. After 18-24 hours, cells were
lysed and the DDR1 phosphorylation was determined by western blot
analysis (A, B) or by capture ELISA (C,D). A representative western blot
of phosphorylated and total DDR1 is shown in A. pDDR1 and DDR1 bands
were quantified as described in the Methods and the values are expressed
as pDDR/DDR1 ratio. Data are the mean ± SEM of 4-6 independent
experiments (B). In C we show 1 representative dose response curve of 4
experiments for pDDR1 inhibition by 1 and 7e. For each fitting curve the
IC50 values of 1 and 7e were different with a p <0.0001. T-test of IC50 values
for 4 experiments were different between 1 and 7e with p=0.0079 (D).
collagen I. After 24 h, the levels of total and phosphorylated
DDR1 were analyzed in cell lysates by Western blot analysis
(Figure 5A). Both 1 and 7e inhibited collagen I-induced DDR1
phosphorylation in a dose dependent manner. However, lower
doses of 7e were required to achieve better inhibition of DDR1
phosphorylation, visible at the lowest dose of 4 nM (Figure 5A
and Figure 5B). To better determine the IC50 values, we used a
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capture ELISA assay using HEK293 cells expressing flagged In summary, we performed
Page 4 of 13
multi-dimensional
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2
3
4
5
6
7
8
human full length DDR1 cDNA (HEK293-DDR1-FLAG)
incubated with inhibitors and collagen I for 18h. Analysis of
the phosphorylated DDR1/total DDR1 ratio revealed an IC50 for
7e of 0.7078±0.3533 nM, while the IC50 for 1 was ~7-fold
weaker at 4.799±2.066 nM. The low IC50s for 1 and 7e confirm
that both compounds are potent inhibitors of DDR1 (Figure 5C
and Figure 5D).
optimization effort around known DDR1/2 dual inhibitor 1, and
quickly identified key elements of a DDR1 pharmacophore.
Targeted optimization then produced 7e (VU6015929), a new
dual DDR1/2 inhibitor with improved binding and cell-based
potency, enhanced physiochemical and DMPK properties and
clean kinome profile to serve as a new in vitro and in vivo tool
compound.
Moreover, 7e was shown to potently inhibit
collagen IV production, further validating a role for DDR1 as
pro-fibrotic receptor. Results from ongoing in vivo work rodent
disease models will be reported in due course.
9
DDR1 is a positive regulator of collagen production, and we
previously showed that activated/phosphorylated DDR1
promotes collagen IV production in kidney mesangial cells;
moreover, we demonstrated that this effect can be inhibited by
1 in a DDR1 dependent manner.6 To determine whether 7e can
also prevent DDR1-mediated collagen IV, we
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AUTHOR INFORMATION
Corresponding Authors
*(CWL). Phone: 1 615-322-8700. Fax: 1 615-936-4381. Email:
craig.lindsley@vanderbilt.edu. *(AP). Phone: 1-615-322-4637.. E-
mail: ambra.pozzi@vumc.org
Author Contributions
CWL and AP drafted/corrected the manuscript and directed the science.
DEJ performed the chemical synthesis. CWL and AP oversaw the
target selection and interpreted the biological data. CMB performed
the in vitro molecular pharmacology studies. ALB performed the in
vitro and in vivo DMPK studies. All authors have given approval to
the final version of the manuscript.
Figure 6. DDR1 inhibitors 1 and 7e block collagen IV production in a
DDR1 dependent manner. Serum-starved DDR1-null mesangial cells
expressing human full length DDR1b cDNA were treated with DMSO, 1 or
7e (both at 3µM) for 24 h and analyzed for the levels of collagen IV (CIV)
and Akt (loading control) by Western blot analysis (A). CIV and Akt bands
were quantified as described in methods. The values are the mean ± SEM
of 3 experiments performed at least in triplicates (*p<0.05, ** p< 0.0001
compared to no-inhibitor cells) (B). Western blot analysis of CIV and FAK
(loading control) levels in serum-starved DDR1-null mesangial cells
expressing human full length DDR1b cDNA treated with DMSO, or DDR1-
null mesangial cells (KO) treated with DMSO or 7e (3µM) for 24 h. CIV
and FAK bands were quantified by densitometry analysis and values are the
mean ± SEM of 1 representative experiment performed in triplicates
(*p<0.05, compared to DDR1b expressing cells).
Acknowledgement
The authors would also like to thank the William K. Warren, Jr.
and the William K. Warren Foundation who funded the William K.
Warren, Jr. Chair in Medicine (to C.W.L.).
ASSOCIATED CONTENT
Supporting Information. General methods for the synthesis and
characterization of all compounds, and methods for the in vitro and
in vivo DMPK protocols and supplemental figures. This material
is available free of charge via the Internet at http://pubs.acs.org.
This work was in part supported by Veterans Affairs Merit Review
1I01BX002025 (AP); National Institute of Health grants R01-
DK119212 (AP, CMB), P30-DK114809 (AP). AP is the recipient
of a VA Senior Research Career Scientist award.
treated serum-starved DDR1-null mesangial cells reconstituted
with human full length DDR1 cDNA with 1 and 7e (both at 3
µM). After 24 h, the levels of collagen IV were analyzed in cell
lysates by Western blot analysis. As shown in Figure 6A, both
1 and 7e significantly inhibited collagen IV production
compared to cells treated with vehicle only; however, with a
lower p value for 7e (Figure 6B). Similar to 1, 7e did not
decrease collagen IV production in the DDR1-null mesangial
cells (data not shown). These results suggest that 7e
(VU6015929) is an improved tool compound over 1 in affecting
DDR1 phosphorylation due to a combination of its enhanced
DDR1 potency and more drug-like physiochemical and DMPK
profiles.
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11. Richter, iH.; Satz, A.L.; Bedoucha, M.; Buettelmann, B.;
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13. See Supporting Information for details.
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Discovery of VU6015929: A selective dual discoidin domain receptor
1/2 (DDR1/2) receptor tyrosine kinase inhibitor to explore the role of
DDR1 in anti-fibrotic therapy
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π
,║
Daniel E. Jeffries,†,π Corina M. Borza,ψ, Anna L. Blobaum, ɸ Ambra Pozzi, ψ, ϒ* and Craig W. Lindsley†, ,║
*
ɸ
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