PMID- 9356485
OWN - NLM
STAT- MEDLINE
DCOM- 19971216
LR  - 20230331
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 94
IP  - 23
DP  - 1997 Nov 11
TI  - ER-27319, an acridone-related compound, inhibits release of antigen-induced 
      allergic mediators from mast cells by selective inhibition of fcepsilon receptor 
      I-mediated activation of Syk.
PG  - 12539-44
AB  - Engagement of the mast cell high-affinity receptor for immunoglobulin E (IgE), 
      FcepsilonRI, induces tyrosine phosphorylation of Syk, a non-receptor tyrosine 
      kinase, that has been demonstrated as critical for degranulation. Herein we 
      describe a synthetic compound, ER-27319, as a potent and selective inhibitor of 
      antigen or anti-IgE-mediated degranulation of rodent and human mast cells. 
      ER-27319 affected neither Lyn kinase activity nor the antigen-induced 
      phosphorylation of the FcepsilonRI but did effectively inhibit the tyrosine 
      phosphorylation of Syk and thus its activity. As a consequence, tyrosine 
      phosphorylation of phospholipase C-gamma1, generation of inositol phosphates, 
      release of arachidonic acid, and secretion of histamine and tumor necrosis factor 
      alpha were also inhibited. ER-27319 did not inhibit the anti-CD3-induced tyrosine 
      phosphorylation of phospholipase C-gamma1 in Jurkat T cells, demonstrating a 
      specificity for Syk-induced signals. In contrast the tyrosine phosphorylation and 
      activation of Syk, induced by in vitro incubation with the phosphorylated 
      immunoreceptor tyrosine-based activation motif (ITAM) of FcepsilonRI gamma 
      subunit or by antigen activation of RBL-2H3 cells, was specifically inhibited by 
      ER-27319. However, when ER-27319 was added to immunoprecipitated Syk, derived 
      from activated cells, no effect was seen on Syk activity. ER-27319 did not 
      inhibit the tyrosine phosphorylation of Syk induced by activation in the presence 
      of Igbeta ITAM or the anti-IgM-induced phosphorylation of Syk in human peripheral 
      B cells. Therefore, ER-27319 selectively interferes with the FcepsilonRI gamma 
      phospho-ITAM activation of Syk in vitro and in intact cells. These results 
      confirm the importance of Syk in FcepsilonRI-mediated responses in mast cells and 
      demonstrate the mast cell selectivity and therapeutic potential of ER-27319 in 
      the treatment of allergic disease.
FAU - Moriya, K
AU  - Moriya K
AD  - Department of Drug Discovery, Tsukuba Research Laboratories, Eisai Company, Ltd., 
      5-1-3 Tokodai, Tsukuba, Ibaraki 30026, Japan.
FAU - Rivera, J
AU  - Rivera J
FAU - Odom, S
AU  - Odom S
FAU - Sakuma, Y
AU  - Sakuma Y
FAU - Muramato, K
AU  - Muramato K
FAU - Yoshiuchi, T
AU  - Yoshiuchi T
FAU - Miyamoto, M
AU  - Miyamoto M
FAU - Yamada, K
AU  - Yamada K
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Acridines)
RN  - 0 (Allergens)
RN  - 0 (Enzyme Precursors)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Receptors, IgE)
RN  - 218W96J218 (ER 27319)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (SYK protein, human)
RN  - EC 2.7.10.2 (Syk Kinase)
SB  - IM
MH  - Acridines/chemistry/*pharmacology
MH  - Allergens/immunology/pharmacology
MH  - Animals
MH  - Cell Degranulation/*drug effects
MH  - Cell Line
MH  - Enzyme Precursors/*immunology
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Mast Cells/*immunology
MH  - Protein-Tyrosine Kinases/*immunology
MH  - Receptors, IgE/*immunology
MH  - Signal Transduction/*drug effects/immunology
MH  - Syk Kinase
PMC - PMC25030
EDAT- 1997/11/14 00:00
MHDA- 1997/11/14 00:01
PMCR- 1998/05/11
CRDT- 1997/11/14 00:00
PHST- 1997/11/14 00:00 [pubmed]
PHST- 1997/11/14 00:01 [medline]
PHST- 1997/11/14 00:00 [entrez]
PHST- 1998/05/11 00:00 [pmc-release]
AID - 2887 [pii]
AID - 10.1073/pnas.94.23.12539 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12539-44. doi: 
      10.1073/pnas.94.23.12539.