Spleen tyrosine kinase inhibition attenuates airway hyperresponsiveness and pollution-induced enhanced airway response in a chronic mouse model of asthma

Penton, Patricia Castellanos; Wang, Xiaomin; Amatullah, Hajera; Cooper, Josephine M.; Godri, Krystal; North, Michelle L.; Khanna, N; Scott, Jeremy A.; Chow, Chung‐Wai

doi:10.1016/j.jaci.2012.07.039

Cited by 30 publications

(38 citation statements)

References 46 publications

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“…These fall into two general categories: small molecule inhibitors of catalytic activity and oligonucleotide-based inhibitors of protein expression. Most small molecule Syk inhibitors, with the exception of the substrate-site inhibitor piceatannol, target the ATP-binding site; several have proven efficacious in blocking inflammation in mouse models of asthma [25–27]. Similarly, inhibitors based on both antisense oligonucleotides and small interfering RNAs (siRNAs) designed to inhibit Syk expression have proven effective in animal models of ovalbumin-induced asthma [28, 29].…”

Section: High Affinity Receptor For Immunoglobulin E (Ige)mentioning

confidence: 99%

Getting Syk: spleen tyrosine kinase as a therapeutic target

Geahlen

2014

Trends in Pharmacological Sciences

203

186

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Syk is a cytoplasmic protein-tyrosine kinase well known for its ability to couple immune cell receptors to intracellular signaling pathways that regulate cellular responses to extracellular antigens and antigen-immunoglobulin complexes of particular importance to the initiation of inflammatory responses. Thus, Syk is an attractive target for therapeutic kinase inhibitors designed to ameliorate symptoms and consequences of acute and chronic inflammation. Its more recently recognized role as a promoter of cell survival in numerous cancer cell types ranging from leukemia to retinoblastoma has attracted considerable interest as a target for a new generation of anticancer drugs. This review discusses the biological processes in which Syk participates that have made this kinase such a compelling drug target. Keywordsprotein kinase inhibitor; tyrosine-phosphorylation; fostamatinib; allergic asthma; rheumatoid arthritis; leukemia Spleen tyrosine kinaseThe central role played by Syk (spleen tyrosine kinase) in the immune system in mediating inflammatory responses, coupled with its more recently identified association with malignancy, has made this kinase a popular target for the development of therapeutic agents. A search of the patent literature reveals over 70 filings describing the development of small molecular inhibitors of Syk for the treatment of multiple disease states ranging from arthritis and asthma to leukemia and lymphoma.Syk catalyzes the phosphorylation of proteins on tyrosines located at sites rich with acidic amino acids [1]. Interestingly, at least two substrates, CD79a [2] and the Ikaros transcription factor [3], have been reported to be phosphorylated by Syk on serine, suggesting that Syk may access a wider distribution of substrates than originally thought. The Syk protein comprises a pair of Src homology 2 (SH2) domains at the N-terminus that are joined to each © 2014 Elsevier Ltd. All rights reserved.Corresponding author: Geahlen, R.L. (geahlen@purdue.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure 1). Aromatic amino acids in linker A, linker B, the catalytic domain and the extreme C-terminus participate in the formation of a "linker-kinase sandwich" (as first identified in the Syk-family member, ) that maintains the enzyme in an autoinhibited conformation [7]. Activation of Syk occurs when the tandem SH2 domains are engaged or when tyrosines participating in the linker-kinase sandwich become phosphorylated. NIH Public AccessSH2 domains are structural motifs that bind phosphotyrosine to promote protein-protein interactions [8]. Each of ...

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Section: High Affinity Receptor For Immunoglobulin E (Ige)mentioning

confidence: 99%

Getting Syk: spleen tyrosine kinase as a therapeutic target

Geahlen

2014

Trends in Pharmacological Sciences

203

186

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“…Role in Asthma and Chronic Obstructive Pulmonary Disease. In a chronic allergic murine model of asthma there was an increase in Syk activation in epithelial cells, and a Syk inhibitor [N-[4-[6-(cyclobutylamino)-9H-purin-2-ylamino]phenyl]-N-methylacetamide (NVP-QAB-205)] significantly reduce AHR after allergen and the enhanced AHR after additional exposure to diesel particulates and ozone, although there was no reduction in inflammatory cells (Penton et al, 2013)…”

Section: Spleen Tyrosine Kinase Inhibitionmentioning

confidence: 99%

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

Barnes

2016

Pharmacol Rev

103

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“…The dose and method of administration of 3,4-methylenedioxy-β-nitrostyrene were chosen based on the results of our concentration gradient pilot study and by referring to relevant studies. 32,33 The control rats received the equivalent vehicle ( Fig. 1).…”

Section: Animal Grouping and Tissue Preparationmentioning

confidence: 99%