A novel druglike spleen tyrosine kinase binder prevents anaphylactic shock when administered orally

J Allergy Clin Immunol. 2008 Jul;122(1):188-94, 194.e1-3. doi: 10.1016/j.jaci.2008.04.026. Epub 2008 Jun 9.

Abstract

Background: The spleen tyrosine kinase (Syk) is recognized as a potential pharmaceutical target for the treatment of type I hypersensitivity reactions including allergic rhinitis, urticaria, asthma, and anaphylaxis because of its critical position upstream of immunoreceptor signaling complexes that regulate inflammatory responses in leukocytes.

Objective: Our aim was to improve the selectivity of anti-Syk therapies by impeding the interaction of Syk with its cellular partners, instead of targeting its catalytic site.

Methods: We have previously studied the inhibitory effects of the anti-Syk intracellular antibody G4G11 on Fc epsilonRI-induced release of allergic mediators. A compound collection was screened by using an antibody displacement assay to identify functional mimics of G4G11 that act as potential inhibitors of the allergic response. The effects of the selected druglike compounds on mast cell activation were evaluated in vitro and in vivo.

Results: We discovered compound 13, a small molecule that inhibits Fc epsilonRI-induced mast cell degranulation in vitro and anaphylactic shock in vivo. Importantly, compound 13 was efficient when administered orally to mice. Structural analysis, docking, and site-directed mutagenesis allowed us to identify the binding cavity of this compound, located at the interface between the 2 Src homology 2 domains and the interdomain A of Syk.

Conclusion: We have isolated a new class of druglike compounds that modulate the interaction of Syk with some of its macromolecular substrates implicated in the degranulation pathway in mast cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Anaphylaxis / immunology
  • Anaphylaxis / prevention & control*
  • Animals
  • Antibodies, Monoclonal / immunology
  • Calcium / metabolism
  • Cell Degranulation
  • Enzyme Activation
  • Female
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / immunology
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mast Cells / immunology*
  • Mast Cells / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / metabolism
  • Passive Cutaneous Anaphylaxis / immunology
  • Protein-Tyrosine Kinases / chemistry
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Receptors, IgE / immunology
  • Signal Transduction
  • Syk Kinase
  • Thiazoles / administration & dosage*
  • Thiazoles / chemistry
  • Thiazoles / metabolism
  • Thiazoles / therapeutic use
  • src-Family Kinases / metabolism

Substances

  • Antibodies, Monoclonal
  • Intracellular Signaling Peptides and Proteins
  • Receptors, IgE
  • Thiazoles
  • methyl-2-(5-((3-benzyl-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene)methyl)-2-furyl)benzoate
  • Protein-Tyrosine Kinases
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn
  • Syk Kinase
  • Syk protein, mouse
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Mitogen-Activated Protein Kinases
  • Calcium