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Inhibitors of cell migration that inhibit intracellular paxillin/alpha a binding: A well-documented use of positional scanning libraries

Academic Article
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Overview

authors

  • Ambroise, Y.
  • Yaspan, B.
  • Ginsberg, Mark
  • Boger, Dale

publication date

  • November 2002

journal

  • Chemistry & Biology  Journal

abstract

  • Screening combinatorial libraries for inhibition of Paxillin binding to the cytoplasmic tail of the integrin alpha4 provided the first inhibitors of this protein-protein interaction implicated in enhanced rates of cell migration and chronic inflammation. The preparation of substructure analogs of the lead identified features required for activity, those available for modification, and those that may be removed. The most potent lead structure was shown to inhibit alpha(4)beta(1)-mediated human Jurkat T cell migration in a dose-dependent manner, validating the intracellular Paxillin/alpha4 interaction as a useful and unique target for therapeutic intervention. Moreover, the lead structure emerged from a library that was prepared in two formats: (1) a traditional small mixture format composed of 100 mixtures of 10 compounds and (2) a positional scanning library. Their parallel testing provided the rare opportunity to critically compare two approaches.

subject areas

  • Chemotaxis, Leukocyte
  • Combinatorial Chemistry Techniques
  • Cytoskeletal Proteins
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Integrin alpha4
  • Jurkat Cells
  • Molecular Structure
  • Paxillin
  • Phosphoproteins
  • Protein Binding
  • Structure-Activity Relationship
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Identity

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/s1074-5521(02)00246-6

PubMed ID

  • 12445772
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Additional Document Info

start page

  • 1219

end page

  • 1226

volume

  • 9

issue

  • 11

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