PMID- 16946104
OWN - NLM
STAT- MEDLINE
DCOM- 20070109
LR  - 20131121
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 319
IP  - 3
DP  - 2006 Dec
TI  - R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor 
      signaling and reduces immune complex-mediated inflammation.
PG  - 998-1008
AB  - 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 (EC(50) 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.
FAU - Braselmann, Sylvia
AU  - Braselmann S
AD  - Rigel Pharmaceuticals, South San Francisco, CA 94080, USA.
FAU - Taylor, Vanessa
AU  - Taylor V
FAU - Zhao, Haoran
AU  - Zhao H
FAU - Wang, Su
AU  - Wang S
FAU - Sylvain, Catherine
AU  - Sylvain C
FAU - Baluom, Muhammad
AU  - Baluom M
FAU - Qu, Kunbin
AU  - Qu K
FAU - Herlaar, Ellen
AU  - Herlaar E
FAU - Lau, Angela
AU  - Lau A
FAU - Young, Chi
AU  - Young C
FAU - Wong, Brian R
AU  - Wong BR
FAU - Lovell, Scott
AU  - Lovell S
FAU - Sun, Thomas
AU  - Sun T
FAU - Park, Gary
AU  - Park G
FAU - Argade, Ankush
AU  - Argade A
FAU - Jurcevic, Stipo
AU  - Jurcevic S
FAU - Pine, Polly
AU  - Pine P
FAU - Singh, Rajinder
AU  - Singh R
FAU - Grossbard, Elliott B
AU  - Grossbard EB
FAU - Payan, Donald G
AU  - Payan DG
FAU - Masuda, Esteban S
AU  - Masuda ES
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20060831
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Lipopolysaccharides)
RN  - 0 
      (N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine)
RN  - 0 (Oxazines)
RN  - 0 (Pyridines)
RN  - 0 (Receptors, Fc)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
EIN - J Pharmacol Exp Ther. 2013 May;345(2):326
MH  - Animals
MH  - Antigen-Antibody Complex/*physiology
MH  - Arthritis, Experimental/pathology
MH  - Arthus Reaction/physiopathology
MH  - B-Lymphocytes/drug effects/physiology
MH  - Basophils/drug effects
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Crystallography
MH  - Double-Blind Method
MH  - Enzyme Inhibitors/pharmacokinetics/*pharmacology
MH  - Fluorescence Polarization Immunoassay
MH  - Humans
MH  - Immunoglobulin G/biosynthesis/immunology
MH  - Inflammation/*drug therapy/pathology
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages/drug effects
MH  - Mast Cells/drug effects
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Oxazines/pharmacokinetics/*pharmacology
MH  - Platelet Aggregation/drug effects
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors
MH  - Pyridines/pharmacokinetics/*pharmacology
MH  - Receptors, Fc/*antagonists & inhibitors
MH  - Signal Transduction/*drug effects
MH  - Spleen/*enzymology
MH  - Stimulation, Chemical
MH  - Tetradecanoylphorbol Acetate/pharmacology
EDAT- 2006/09/02 09:00
MHDA- 2007/01/11 09:00
CRDT- 2006/09/02 09:00
PHST- 2006/09/02 09:00 [pubmed]
PHST- 2007/01/11 09:00 [medline]
PHST- 2006/09/02 09:00 [entrez]
AID - jpet.106.109058 [pii]
AID - 10.1124/jpet.106.109058 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2006 Dec;319(3):998-1008. doi: 10.1124/jpet.106.109058. 
      Epub 2006 Aug 31.