title: Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis.
abstract: Based on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC50 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC50 0.27 and 0.28 μM, respectively) and Fcε receptor 1-mediated basophil degranulation (IC50 0.15 μM). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC50 0.32 μM). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by ∼67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.
authors: Portola Pharmaceuticals, South San Francisco, CA 94080, USA.
authors: Greg
authors: G
authors: Coffey
authors: Francis
authors: F
authors: DeGuzman
authors: Mayuko
authors: M
authors: Inagaki
authors: Yvonne
authors: Y
authors: Pak
authors: Suzanne M
authors: SM
authors: Delaney
authors: Dan
authors: D
authors: Ives
authors: Andreas
authors: A
authors: Betz
authors: Zhaozhong J
authors: ZJ
authors: Jia
authors: Anjali
authors: A
authors: Pandey
authors: Dale
authors: D
authors: Baker
authors: Stanley J
authors: SJ
authors: Hollenbach
authors: David R
authors: DR
authors: Phillips
authors: Uma
authors: U
authors: Sinha
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001491:Basophils / Q000187:drug effects / Q000276:immunology; D055162:Biocatalysis / Q000187:drug effects; D001769:Blood / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003514:Cyclohexylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004487:Edema / Q000150:complications / Q000473:pathology / Q000517:prevention & control; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005528:Foot / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D011947:Receptors, Antigen, B-Cell / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000072377:Syk Kinase; D013585:Synovitis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C571149:4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-(2-aminocyclohexylamino)pyrimidine-5-carboxamide; D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D003514:Cyclohexylamines; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases