Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness

Article abstract of DOI:10.1016/j.bmcl.2020.127578

Inhibition of integrin α5β1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5β1 by backbone replacement of known αvβ1 integrin inhibitors. These integrin α5β1 inhibitors also retain the nanomolar potency against αvβ1 integrin, which shows promise for developing dual integrin α5β1/αvβ1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvβ3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5β1 inhibitors as potential novel asthma therapeutics.

Full text of DOI:10.1016/j.bmcl.2020.127578

Journal Pre-proofs
Dual antagonists of α5β1/ αvβ1 integrin for airway hyperresponsiveness
Aparna Sundaram, Chun Chen, Nilgun Isik Reed, Sean Liu, Seul Ki Yeon,
Joel McIntosh, You-Zhi Tang, Hyunjun Yang, Marc Adler, Richard Beresis,
Ian B. Seiple, Dean Sheppard, William F. DeGrado, Hyunil Jo
PII:
S0960-894X(20)30689-2
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127578
BMCL 127578
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
8 July 2020
18 September 2020
21 September 2020
Please cite this article as: Sundaram, A., Chen, C., Isik Reed, N., Liu, S., Ki Yeon, S., McIntosh, J., Tang, Y-Z.,
Yang, H., Adler, M., Beresis, R., Seiple, I.B., Sheppard, D., DeGrado, W.F., Jo, H., Dual antagonists of α5β1/
αvβ1 integrin for airway hyperresponsiveness, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://
doi.org/10.1016/j.bmcl.2020.127578
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© 2020 Published by Elsevier Ltd.

Dual antagonists of α5β1/ αvβ1 integrin for airway
hyperresponsiveness
Aparna Sundarama, Chun Chenb, Nilgun Isik Reeda, Sean Liuc, Seul Ki Yeond, Joel
McIntoshd,1, You-Zhi Tangd,2, Hyunjun Yangd, Marc Adlere, Richard Beresise, Ian B.
Seipled, Dean Shepparda, William F. DeGradod, Hyunil Jod,*
aSchool of Medicine, University of California San Francisco, San Francisco, CA 94158,
USA
bPliant Therapeutics, 260 Littlefield Ave, South San Francisco, CA 94080, USA
cLung Biology Center, Department of Medicine, University of California San Francisco,
San Francisco, CA 94158, USA
dDepartment of Pharmaceutical Chemistry, University of California San Francisco, San
Francisco, CA 94158, USA
eChemPartner, 280 Utah Avenue, South San Francisco, CA 94080, USA
1Present address: Nurix Therapeutics, 1700 Owens Street, San Francisco, CA 94158,
USA
2Present address: College of Veterinary Medicine, South China Agricultural University,
Guangzhou, 510642, China
*Corresponding author: Hyunil.Jo@ucsf.edu
1

Abstract
Inhibition of integrin alpha5beta1 emerges as a novel therapeutic option to block
transmission of contractile forces during asthma attack. We designed and synthesized
novel inhibitors of integrin alpha5beta1 by backbone replacement of known alphavbeta1
integrin inhibitors. These integrin alpha5beta1 inhibitors also retain the nanomolar
potency against alphavbeta1 integrin, which shows promise for developing dual integrin
alpha5beta1/alphavbeta1 inhibitor. Introduction of hydrophobic adamantane group
significantly boosted the potency as well as selectivity over integrin alphavbeta3. We
also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in Ex
vivo mouse tracheal ring assay. Results from this study will help guide further
development of integrin alpha5beta1 inhibitors as potential novel asthma therapeutics.
Keywords: Integrin alpha5beta1, Integrin alphavbeta1, Integrin inhibitor, RGD integrin,
asthma
2

Graphical Abstract
O
H
O
N
NH2
NH
NH
NH2
H
N
N
H
NH
N
O
PhO2S
H
4
O
Linker
O
N
SO2
N
CO2H
H
N
N
CO2H
H
RGD-Integrin inhibitor
(alphavbeta1)
Dual RGD-Integrin inhibitor
(alphavbeta1/alpha5beta1)
3

Airway hyperresponsiveness (AHR) - excessive narrowing of airway in response to
stimulus is the hallmark feature of asthma.1 Most patients with asthma can benefit from
anti-inflammatory agents and inhibitors of smooth muscle contraction to reduce AHR.2
However, severe asthma still remains difficult to control and affects up to 10% of
patients with asthma.3 Although biologics targeting disease-relevant cytokines in the
inflammation process have recently emerged as add-on therapies, this approach is
hindered by targeting only a limited subset of asthma patients (T2-high) as well as
imposing a significant economic burden on the individual, family, and society.4-5 Thus,
there remains an urgent need to accelerate a novel therapeutic approaches to treat
severe asthma.
Our groups have previously shown that reduction of AHR could be achieved by
pharmacological inhibition of integrins.6 Integrins are heterodimeric transmembrane
proteins consisting of alpha and beta subunits that are involved in several critical cell
processes including anchorage, migration, remodeling, and signaling.7 They are the
principal receptors used by cells to link the actin cytoskeleton with adjacent extracellular
matrix (ECM) proteins, including fibronectin and collagens.8 In airway tissue, this
integrin-ECM interaction plays a crucial role in force transmission and airway smooth
muscle (ASM) cell proliferation ultimately leading to exaggerated airway narrowing. We
demonstrated that inhibition of the α5β1 integrin binding to fibronectin resulted in
marked decrease of AHR in an ovalbumin-challenged mouse model of asthma. Our
work also revealed that integrin inhibition has an additive effect when combined with
currently available β-adrenergic agonists, which suggested the potential use of integrin
inhibitors as adjuvant therapy to standard bronchodilators. However, the tool peptide
4

(ATN-161)9 used in our study suffered from low potency and exhibited low plasma
stability. For this reason, we sought to identify novel small molecule inhibitors against
the α5β1 integrin.
The α5β1 integrin has been previously proposed as an attractive therapeutic
target in cancer therapy10 due to its effects on inhibiting angiogenesis, and there are
several small molecule inhibitors against the α5β1 integrin described in the literature.11-
14
In the initial activity profiling of these known inhibitors (1-3), we found they displayed
poor selectivity against the αvβ3 integrin and micromolar potency for α5β1 integrin in
our cell adhesion assay15. We next turned our attention to our αvβ1 integrin inhibitor
series16 and backbone replacement from phenylalanine with 2,3-diaminopropionic acid
(DAP) was shown to influence the selectivity toward alpha5beta1 significantly (Figure 1).
For example, 5 (DAP analogs of the selective αvβ1 integrin inhibitor 4) exhibited sub-
micromolar IC50 against α5β1 integrin while maintaining sub-nanomolar potency against
αvβ1 integrin in the cell adhesion assay. Moreover, 5 still displayed excellent selectivity
against αvβ3 integrin, which encouraged us to further investigate the DAP scaffold
towards dual α5β1/αvβ1 integrin inhibitors. From dual mode of inhibition, it was
anticipated that αvβ1 integrin inhibition could add benefit to AHR by reducing cytokine
release in ASM.17
5

O
O
O
HO
O
O
HO
O
NH
HN
O
O
N
N
H
NH
Cl
H
O
N
N
H
N
N
N
N
OH
N
Cl
H
O
O
2
1
3
H
H
N
N
NH2
NH
H
H
N
H
N
N
NH2
O
SO2
O
O
SO2
O
NH
N
N
CO2H
N
H
N
CO2H
H
4
5
IC50 (nM)
IC50 (nM)
v1: 0.5
51: >10000
v3: >10000
v1: 0.8
51: 500
v3: >10000
Figure 1. Structures of α5β1 integrin inhibitors 1-3 and αvβ1 integrin inhibitors 4-5
For design of a dual inhibitor, we synthesized a handful of analogs of 5 using
conventional chemistry to explore the linker effect in DAP scaffold (Scheme 1). Thus,
commercially available Boc-protected L-2,3-diaminopropionic acid methyl ester 6 was
coupled with benzenesulfonyl-L-proline to provide amine 7 after deprotection of Boc
protecting group under acidic condition. Reaction of the common intermediate amine 7
with Boc-protected -guanidino p-nitrophenylchloro carbamate yielded the urea series
(8-10) after deprotection and hydrolysis. Similarly, coupling of amine 7 with N-Boc-
protected carboxylic acids provided amides (11-15) after TFA removal of Boc group
followed by mild hydrolysis with LiOH and HPLC purification.
O
OH
O
OMe
NH3+Cl-
c,g,h
NH
NH2
O
OMe
NHBoc
O
O
PhO2S
PhO2S
a,b
H
L
or
d, e-h
N
N
N
N
N
H
N
H
H2N
H
O
6
7
8-15
Scheme 1 Synthesis of 8-15 Reagents and Conditions: a) N-benzenesulfonyl-L-proline, HCTU, DIPEA, b)
4M HCl in dioxane (70% for the two steps) c) RNHCO2PhNO2, DIPEA or R’CO2H, HCTU, DIPEA, d) Boc-
6

Gly, HCTU, DIPEA e) 4M HCl in dioxane f) R’’CO2H, HCTU, DIPEA g) TFA, DCM h) LiOH, THF-H2O. See
the Supplementary data for details of syntheses.
8-15 were then tested against three integrins - α5β1, αvβ1, and αvβ3 for their
potency and selectivity (Table 1). Among the compounds with simple alkyl linkers
between DAP and the terminal phenylguanidine moiety, higher potency was observed
for 6-atom linker (compound 5). Increase of linker rigidity by introduction of phenyl ring
further boosted the potency (compound 11-15) toward α5β1 integrin. While amide linker
for DAP (compound 10) is preferred for α5β1 integrin inhibition, urea linker (compound 8)
showed much higher potency against αvβ1 integrin. Thus, presence of additional
hydrogen bond donor in urea linker could fine tune the selectivity between α5β1 and
αvβ1 integrin. On the other hand, a huge increase of potency against α5β1 integrin was
observed in rigid m-phenyl guanidine compound 11 and 12. Glycine-linked compound
11 is particularly promising for development of a dual inhibitor as it exhibits comparable
potency for both α5β1 and αvβ1 integrin. It is also worth mentioning aza-glycine linker
compound 12 favors α5β1 integrin as suggested by previous works.11-12 While the
potency was improved more than 10-fold in compound 11 or 12, selectivity over αvβ3
integrin was not still satisfactory in either 11 or 12. Surprisingly, a dramatic increase of
selectivity over αvβ3 integrin was achieved by substituted m-phenylguanidine series
(compound 13-15). We chose an amide linker for phenyl ring substitution due to its
facile synthesis and introduced additional alkyl chain to increase lipophilicity. Either
hydrophobic alkyl amide substitution (13) or positively charged alkyl amide substitution
(14) boosts the selectivity but did not increase the potency against α5β1 integrin. The
best compound was 15 containing 1-adamantyl group to mask the amine. Compound
15 not only showed great selectivity over αvβ3 integrin but also exhibited excellent
7

nanomolar potency for α5β1 and sub-nanomolar potency for αvβ1 integrin. Since all the
amide compounds 13-15 shared the same feature in amide linker on the phenyl ring, we
speculated that adamantane at the terminal position played a key role in improvement
of potency.
O
OH
NH
NH2
O
PhO2S
H
L
N
N
N
N
H
H
O
IC50 (nM) ± SD
ID
5
L
α5β1
αvβ1
αvβ3
H
N
501±90
0.8±0.2
4±0.8
6,800±500
H
N
8
9,700±900
900±150
830±20
>100,000
15,000±930
10,000±790
H
N
9
0.9±0.2
316±80
10
11
O
40±18
50±20
32±8
1,100±200
6,500±900
N
H
O
H
12
N
158±20
N
H
O
N
Not
tested
HN
13
14
110±24
32±6
16,800±400
H
R =
6
O
R
O
N
Not
tested
HN
56,000±2,000
H
R =
3 NH2
O
R
O
O
N
HN
R =
15
2.6±0.9
0.8±0.1
8,800±15
H
Amt
N
3
H
O
R
Table 1. Cell adhesion assay for a5b1 integrin inhibitors The measurement of cell adhesion
was performed according to the published procedure.15 SW480 plated on fibronectin (0.3 µg/ml)
was used for α5β1 assay and CHOαv adhering to fibronectin (0.3 µg/ml) was used for αvβ1. For
8

αvβ3, SW480 transfected with human β3 adhering to fibrinogen (1 µg/ml) was used. Data
represent means ± S.D.; n = 3 or higher
In order to test if there is a specific binding site for adamantane in α5β1 integrin,
we synthesized a series of adamantane analogs with varied length of alkyl chain and
tested them in solid-phase binding assay (Table 2). A solid-phase binding assay was
used to compare the binding affinity to different integrins without the influence of cellular
factors affecting the cell adhesion assay. All the synthesized adamantane compounds
15-19 showed single-digit nanomolar IC50s against both α5β1 and αvβ1 integrin. The
linker length did not influence the potency and it was speculated that adamantane
moiety induce non-specific binding. Furthermore, we also ruled out any specific
hydrogen bonding patterns since reverse amide 18 or amide 15 showed comparable
potency. Interestingly, the selectivity appears to decrease among αv integrins as the
linker length increased.
O
OH
O
O
PhO2S
H
H
N
N
NH2
NH
N
N
H
N
H
O
HN
R
O
IC50 (nM) ± SD
ID
R
α5β1
αvβ1
αvβ3
αvβ5
αvβ6
αvβ8
α4β1
O
O
O
0.8±0.2
1.6±0.1
1.4±0.1
1.0±0.1
0.7±0.3
0.14±0.01
< 0.1
>10000
>10000
>10000
>10000
>10000
3002±1240
>10000
2762±84
>10000
105±12
15
16
17
18
19
N
Amt
Amt
3H
>10000
>10000
>10000
1867±56
>10000
>10000
136±47
100±30
161±32
182±44
N
H
< 0.1
>10000
N
Amt
Amt
2H
H
N
0.3±0.2
< 0.1
980±320
320±1.8
>10000
3
O
O
6832±470
N
Amt
4H
Table 2. Solid phase binding assay of adamantane analogs 15-19. See the Supplementary
data for details. Data represent means ± S.D.; n = 3
9

Though we cannot exclude the possibility of integrin internalization pathway /
degradation by hydrophobic adamantane for the increased potency,18-19 it appears that
combination of alkyl chain and adamantane moiety might increase integrin binding
affinity through hydrophobic interaction. Hydrophobic interaction may also explain the
superior selectivity over αvβ3 integrin. Computational docking study that showed
hydrophobic moiety is not favored in αvβ3 integrin due to the presence of multiple polar
residues (Tyr, Asp) in αvβ3 integrin (Figure 2). Further studies on the selectivity among
different RGD integrins and different hydrophobic groups are currently underway in our
laboratory. It is also remarkable that these adamantane-containing compounds 15-19
showed much improved selectivity (>100 fold) against α4β1 integrin while our previous
potent αvβ1 inhibitor 4 demonstrated marginal selectivity.20
10

A)
B)
Figure 2. A model of 17 (orange) bound to α5β1. The model is based on the published α5β1
structure 4wk0.pdb and has been minimized using MOE/CCG. A) Connelly surface of the
model. The green patch shows selected hydrophobic side chains of α5: Phe155, Trp157,
Ala159, & Phe187. B) Same α5β1 model (green) shown as above w/o surface. The cyan
atoms represent the crystal structure of αvβ3, 3ije.pdb. Four hydrophilic substitutions are
highlighted in the αv chain that attenuate the affinity for the adamantine group in 17.
With potent dual inhibitors in hands, we also tested activity of compound 11 in an ex
vivo ring contraction assay (Figure 3). This assay measures the force generated by
mouse tracheal rings in response to increasing doses of the contractile agonist
methacholine. The advantage to this functional assay is the ability to see the effect of
integrin inhibition on a tissue level. We observed that treatment with the inhibitor caused
11

a dose-dependent decrease in cytokine-enhanced contraction. It is also worth noting
that inhibition of contraction was observed even in the concentration lower than IC50 in
cell adhesion assay.
Figure 2. Mouse trachea ring contraction assay Force exerted on WT mouse tracheal rings
measured after incubation for 12 h with IL-13 (100 ng/mL), then 1 h with compound 11 or
vehicle with a range of concentrations of methacholine. Negative controls without IL-13
treatment are also shown. n=3 rings per group. **P<0.01, repeated measures of variance.
Unfortunately, our inhibitors showed suboptimal pharmacokinetic properties. For
example, one of our promising compounds 15 showed limited solubility and poor
permeability in Caco-2 cell assay (Papp (A-B/B-A, x10-6 cm/s) = 0.37/0.27). Since airway
smooth muscle resides under epithelial layer of the lung, compounds with low cell
permeability are not favored for in vivo assessment in mouse mode. Further
optimization to improve physicochemical and pharmacokinetic properties is in progress.
In summary, highly potent dual inhibitors for α5β1/αvβ1 integrin based on DAP were
identified. Excellent selectivity over αvβ3 integrin by boosting α5β1 potency was
achieved using an adamantane moiety and we hope this study could provide additional
insight to design better inhibitors against α5β1 and αvβ1 integrin.
12

Declaration of Competing Interest
W.F.D. and D. S. have an equity interest in Pliant Therapeutics which conducts work in
a similar area of research. W.F.D. and D.S. are founders and scientific advisory board
members and C.C. is an employee of Pliant Therapeutics.
Acknowledgements
We (W.F.D. and D.S) would like to thank NIH (UH2HL123423) as well as UCCAI
program (U54HL119893 CFDA NO.93.837/UCSF RAS Award# 122727) for support of
this work. We are also grateful for generous support from ShangPharma Innovation-
UCSF collaboration.
Supplementary data
Supplementary data to this article can be found online at xx.xxxxx.
13

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Declaration of interests
☐ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
W.F.D. and D. S. have an equity interest in Pliant Therapeutics which conducts work in a
similar area of research. W.F.D. and D.S. are founders and scientific advisory board
members and C.C. is an employee of Pliant Therapeutics.
15

16