QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.106.109058v1 319/3/998    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Braselmann, S. Articles by Masuda, E. S. Search for Related Content PubMed PubMed Citation Articles by Braselmann, S. Articles by Masuda, E. S.

INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation

Rigel Pharmaceuticals, South San Francisco, California (S.B., V.T., H.Z., S.W., C.S., M.B., K.Q., E.H., A.L., C.Y., B.R.W., T.S., G.P., A.A., P.P., R.S., E.B.G., D.G.P., E.S.M.); deCODE biostructures, Woodridge, Illinois (S.L.); and King's College London, Department of Nephrology and Transplantation, Guy's Hospital, London, United Kingdom (S.J.)

Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC₅₀ for degranulation = 56–64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (K_i = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.

Address correspondence to: Dr. Esteban S. Masuda, Rigel Pharmaceuticals, 1180 Veterans Blvd, South San Francisco, CA 94080. E-mail: emasuda{at}rigel.com

This article has been cited by other articles:

				I. Valera, N. Fernandez, A. G. Trinidad, S. Alonso, G. D. Brown, A. Alonso, and M. S. Crespo Costimulation of Dectin-1 and DC-SIGN Triggers the Arachidonic Acid Cascade in Human Monocyte-Derived Dendritic Cells J. Immunol., April 15, 2008; 180(8): 5727 - 5736. [Abstract] [Full Text] [PDF]

				P. Huang, D. A. Goff, Q. Huang, A. Martinez, X. Xu, S. Crowder, S. D. Issakani, E. Anderson, N. Sheng, P. Achacoso, et al. Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication Antimicrob. Agents Chemother., April 1, 2008; 52(4): 1419 - 1429. [Abstract] [Full Text] [PDF]

				L. Chen, S. Monti, P. Juszczynski, J. Daley, W. Chen, T. E. Witzig, T. M. Habermann, J. L. Kutok, and M. A. Shipp SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma Blood, February 15, 2008; 111(4): 2230 - 2237. [Abstract] [Full Text] [PDF]

				Y. Yamaguchi, N. Seta, J. Kaburaki, K. Kobayashi, E. Matsuura, and M. Kuwana Excessive exposure to anionic surfaces maintains autoantibody response to 2-glycoprotein I in patients with antiphospholipid syndrome Blood, December 15, 2007; 110(13): 4312 - 4318. [Abstract] [Full Text] [PDF]

				D. N. Forthal, G. Landucci, J. Bream, L. P. Jacobson, T. B. Phan, and B. Montoya Fc{gamma}RIIa Genotype Predicts Progression of HIV Infection J. Immunol., December 1, 2007; 179(11): 7916 - 7923. [Abstract] [Full Text] [PDF]