Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1

Peter Vanderslice, Darren G. Woodside, Amy R. Caivano, E. Radford Decker, Christy L. Munsch, Sidney J. Sherwood, Wanda S. LeJeune, Yuko J. Miyamoto, Bradley W. McIntyre, Ronald Tilton, Richard A F Dixon

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The development of antagonists to the α4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for α4β1 (VLA-4) as well as several dual antagonists that inhibit both α4β1 and α4β7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the α4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of α4β1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule α4 integrin antagonist selective for α4β1 over α4β7 and, specifically, selective for the high affinity conformation of α4β1 may prove to be an effective therapy for multiple inflammatory diseases in humans.

Original languageEnglish (US)
Pages (from-to)619-624
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume400
Issue number4
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

Integrins
Conformations
Inflammation
Integrin alpha4beta1
Molecules
Chemical activation
T-cells
Flow cytometry
Cell Adhesion Molecules
Amides
Autoimmune Diseases
Epitopes
Assays
Flow Cytometry
Animals
Adhesion
Animal Models
Clinical Trials
Ligands
T-Lymphocytes

Keywords

  • Cell trafficking
  • Eosinophils
  • Inflammation
  • Integrin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Vanderslice, P., Woodside, D. G., Caivano, A. R., Decker, E. R., Munsch, C. L., Sherwood, S. J., ... Dixon, R. A. F. (2010). Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1. Biochemical and Biophysical Research Communications, 400(4), 619-624. https://doi.org/10.1016/j.bbrc.2010.08.114

Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1. / Vanderslice, Peter; Woodside, Darren G.; Caivano, Amy R.; Decker, E. Radford; Munsch, Christy L.; Sherwood, Sidney J.; LeJeune, Wanda S.; Miyamoto, Yuko J.; McIntyre, Bradley W.; Tilton, Ronald; Dixon, Richard A F.

In: Biochemical and Biophysical Research Communications, Vol. 400, No. 4, 01.10.2010, p. 619-624.

Research output: Contribution to journalArticle

Vanderslice, P, Woodside, DG, Caivano, AR, Decker, ER, Munsch, CL, Sherwood, SJ, LeJeune, WS, Miyamoto, YJ, McIntyre, BW, Tilton, R & Dixon, RAF 2010, 'Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1', Biochemical and Biophysical Research Communications, vol. 400, no. 4, pp. 619-624. https://doi.org/10.1016/j.bbrc.2010.08.114
Vanderslice, Peter ; Woodside, Darren G. ; Caivano, Amy R. ; Decker, E. Radford ; Munsch, Christy L. ; Sherwood, Sidney J. ; LeJeune, Wanda S. ; Miyamoto, Yuko J. ; McIntyre, Bradley W. ; Tilton, Ronald ; Dixon, Richard A F. / Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1. In: Biochemical and Biophysical Research Communications. 2010 ; Vol. 400, No. 4. pp. 619-624.
@article{b4dab49ab5ac4f1ca8562bcf4c514159,
title = "Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1",
abstract = "The development of antagonists to the α4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for α4β1 (VLA-4) as well as several dual antagonists that inhibit both α4β1 and α4β7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the α4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of α4β1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule α4 integrin antagonist selective for α4β1 over α4β7 and, specifically, selective for the high affinity conformation of α4β1 may prove to be an effective therapy for multiple inflammatory diseases in humans.",
keywords = "Cell trafficking, Eosinophils, Inflammation, Integrin",
author = "Peter Vanderslice and Woodside, {Darren G.} and Caivano, {Amy R.} and Decker, {E. Radford} and Munsch, {Christy L.} and Sherwood, {Sidney J.} and LeJeune, {Wanda S.} and Miyamoto, {Yuko J.} and McIntyre, {Bradley W.} and Ronald Tilton and Dixon, {Richard A F}",
year = "2010",
month = "10",
day = "1",
doi = "10.1016/j.bbrc.2010.08.114",
language = "English (US)",
volume = "400",
pages = "619--624",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin α4β1

AU - Vanderslice, Peter

AU - Woodside, Darren G.

AU - Caivano, Amy R.

AU - Decker, E. Radford

AU - Munsch, Christy L.

AU - Sherwood, Sidney J.

AU - LeJeune, Wanda S.

AU - Miyamoto, Yuko J.

AU - McIntyre, Bradley W.

AU - Tilton, Ronald

AU - Dixon, Richard A F

PY - 2010/10/1

Y1 - 2010/10/1

N2 - The development of antagonists to the α4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for α4β1 (VLA-4) as well as several dual antagonists that inhibit both α4β1 and α4β7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the α4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of α4β1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule α4 integrin antagonist selective for α4β1 over α4β7 and, specifically, selective for the high affinity conformation of α4β1 may prove to be an effective therapy for multiple inflammatory diseases in humans.

AB - The development of antagonists to the α4 integrin family of cell adhesion molecules has been an active area of pharmaceutical research to treat inflammatory and autoimmune diseases. Presently being tested in human clinical trials are compounds selective for α4β1 (VLA-4) as well as several dual antagonists that inhibit both α4β1 and α4β7. The value of a dual versus a selective small molecule antagonist as well as the consequences of inhibiting different affinity states of the α4 integrins have been debated in the literature. Here, we characterize TBC3486, a N,N-disubstituted amide, which represents a unique structural class of non-peptidic, small molecule VLA-4 antagonists. Using a variety of adhesion assay formats as well as flow cytometry experiments using mAbs specific for certain activation-dependent integrin epitopes we demonstrate that TBC3486 preferentially targets the high affinity conformation of α4β1 and behaves as a ligand mimetic. The antagonist is capable of blocking integrin-dependent T-cell co-activation in vitro as well as proves to be efficacious in vivo at low doses in two animal models of allergic inflammation. These data suggest that a small molecule α4 integrin antagonist selective for α4β1 over α4β7 and, specifically, selective for the high affinity conformation of α4β1 may prove to be an effective therapy for multiple inflammatory diseases in humans.

KW - Cell trafficking

KW - Eosinophils

KW - Inflammation

KW - Integrin

UR - http://www.scopus.com/inward/record.url?scp=77957280268&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957280268&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2010.08.114

DO - 10.1016/j.bbrc.2010.08.114

M3 - Article

VL - 400

SP - 619

EP - 624

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 4

ER -