title: GLEPP1/protein-tyrosine phosphatase phi inhibitors block chemotaxis in vitro and in vivo and improve murine ulcerative colitis.
abstract: We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase . Two previously described GLEPP1 substrates, paxillin and Syk, are both required for cytoskeletal rearrangement and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1 inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and block primary human monocyte and mouse bone marrow-derived macrophage chemotaxis in a gradient of monocyte chemotactic protein-1. In mice, the GLEPP1 inhibitors also reduce thioglycolate-induced peritoneal chemotaxis of neutrophils, lymphocytes, and macrophages. In murine disease models, the GLEPP1 inhibitors significantly reduce severity of contact hypersensitivity, a model for allergic dermatitis, and dextran sulfate sodium-induced ulcerative colitis, a model for inflammatory bowel disease. Taken together, our data provide confirmation that GLEPP1 plays an important role in controlling chemotaxis of multiple types of leukocytes and that pharmacological inhibition of this phosphatase may have therapeutic use.
authors.affiliation: Merck Serono International, 9 Chemin des Mines, 1211 Geneva, Switzerland.
authors.forename: Rosanna Pescini
authors.initials: RP
authors.lastname: Gobert
authors.forename: Monique
authors.initials: M
authors.lastname: van den Eijnden
authors.forename: Cedric
authors.initials: C
authors.lastname: Szyndralewiez
authors.forename: Catherine
authors.initials: C
authors.lastname: Jorand-Lebrun
authors.forename: Dominique
authors.initials: D
authors.lastname: Swinnen
authors.forename: Linfeng
authors.initials: L
authors.lastname: Chen
authors.forename: Corine
authors.initials: C
authors.lastname: Gillieron
authors.forename: Fiona
authors.initials: F
authors.lastname: Pixley
authors.forename: Pierre
authors.initials: P
authors.lastname: Juillard
authors.forename: Patrick
authors.initials: P
authors.lastname: Gerber
authors.forename: Caroline
authors.initials: C
authors.lastname: Johnson-Léger
authors.forename: Serge
authors.initials: S
authors.lastname: Halazy
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.forename: Agnes
authors.initials: A
authors.lastname: Bombrun
authors.forename: Margaret
authors.initials: M
authors.lastname: Shipp
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Vitte
authors.forename: Vittoria
authors.initials: V
authors.lastname: Ardissone
authors.forename: Chiara
authors.initials: C
authors.lastname: Ferrandi
authors.forename: Dominique
authors.initials: D
authors.lastname: Perrin
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Rob
authors.initials: R
authors.lastname: Hooft van Huijsduijnen
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000187:drug effects*; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D009000:Monocytes / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000009:adverse effects / Q000737:chemistry*; D015398:Signal Transduction; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D013864:Thioglycolates; D010744:Phosphoric Monoester Hydrolases; C516888:PTPRO protein, human; D017027:Protein Tyrosine Phosphatases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3