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 G. Tilton, Richard A.F. Dixon

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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
Issue number4
StatePublished - Oct 1 2010
Externally publishedYes


  • Cell trafficking
  • Eosinophils
  • Inflammation
  • Integrin

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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