Tyrosine kinase inhibitors: a new approach for asthma

Wong, W.S. Fred; Leong, Khai Pang

doi:10.1016/j.bbapap.2003.11.013

Cited by 82 publications

(65 citation statements)

References 200 publications

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“…[13,14] Furthermore, tyrosine 130 in the inter-SH2 linker of Syk tSH2 plays a crucial role in binding to the B cell antigen receptor and receptor activation. [15] In view of the high specificity and affinity of bivalent ligands for tSH2, the development of inhibitors of Syk kinase activation would be a very attractive strategy for the treatment of allergic diseases such as asthma [16][17][18] and of breast cancer. [3] Our group has been working on ITAM-based peptidomimetics.…”

Section: Introductionmentioning

confidence: 99%

Protein Flexibility and Ligand Rigidity: A Thermodynamic and Kinetic Study of ITAM‐Based Ligand Binding to Syk Tandem SH2

et al. 2005

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The Syk tandem Src homology 2 domain (Syk tSH2) constitutes a flexible protein module involved in the regulation of Syk kinase activity. The Syk tSH2 domain is assumed to function by adapting the distance between its two SH2 domains upon bivalent binding to diphosphotyrosine ligands. A thermodynamic and kinetic analysis of ligand binding was performed by using surface plasmon resonance (SPR). Furthermore, the effect of binding on the Syk tSH2 structural dynamics was probed by hydrogen/deuterium exchange and electrospray mass spectrometry (ESI‐MS). Two ligands were studied: 1, a flexible peptide derived from the tSH2 recognition ITAM sequence at the γ chain of the FcεRI‐receptor, and 2, a ligand in which the amino acids between the two SH2 binding motifs in ligand 1 have been replaced by a rigid linker of comparable length. Both ligands display comparable affinity for Syk tSH2 at 25 °C, yet a major difference in thermodynamics is observed. Upon binding of the rigid ligand, 2, the expected entropy advantage is not realized. On the contrary, 2 binds with a considerably higher entropy price of ∼9 kcal mol−1, which is attributed to a further decrease in protein flexibility upon binding to this rigid ligand. The significant reduction in deuterium incorporation in the Syk tSH2 protein upon binding of either 1 or 2, as monitored by ESI‐MS, indicates a major reduction in protein dynamics upon binding. The results are consistent with a two‐step binding model: after an initial binding step, a rapid structural change of the protein occurs, followed by a second binding step. Such a bivalent binding model allows high affinity and fast dissociation kinetics, which are very important in transient signal‐transduction processes.

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Section: Introductionmentioning

confidence: 99%

Protein Flexibility and Ligand Rigidity: A Thermodynamic and Kinetic Study of ITAM‐Based Ligand Binding to Syk Tandem SH2

et al. 2005

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“…However, several studies have shown that blockade of the estrogen receptor pathway partially abolishes the action of genistein. Genistein is known to be a broad -spectrum protein tyrosine kinase inhibitor (30), and its activity may contribute to one of the estrogen receptor -independent mechanisms. In vitro experiments have shown that genistein at a dose of more than 10 μM inhibits both tyrosine phosphorylation and binding of the nuclear factor to the specific promoter region, resulting in inhibition of proliferation response and cytokine production.…”

Section: Mechanisms Of the Effects Of Ge-nistein On Immune Functionsmentioning

confidence: 99%

Soy isoflavones and immunity

2008

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: The amount of soy products consumed in Japan is much greater than that in Western countries. Recent evidence indicates that soy isoflavones play a beneficial role in obesity, cancer, osteoporosis, and cardiovascular disease. The soybean isoflavone genistein is present at high levels in soy products. Genistein is structurally similar to 17! -estradiol (E2), and genistein has been suggested to be act as E2 or an antagonist against E2. Genistein suppresses antigen-specific immune response in vivo and lymphocyte proliferation response in vitro. However, genistein enhances the cytotoxic response mediated by NK and cytotoxic T cells and the cytokine production from T cells. Thus, the effect of genistein on immunity is immune cell -dependent. Due to its unique effect on immune function, genistein has been used for the treatment of the diseases in animal models and it has been found that genistein inhibits allergic inflammatory responses. In this review, we summarize current studies related to the effect of isoflavone genistein on the immune system.

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“…A number of studies have concentrated on the effect of blocking nonreceptor tyrosine kinases in inflammatory cells (as reviewed by WONG and LEONG [247]). Binding of allergen to immunoceptors causes stimulation of nonreceptor tyrosine kinases, such as Lyn, Lck, Syk and Fyn.…”

Section: Egf/egfr As a Novel Therapeutic Target In Chronic Asthmamentioning

confidence: 99%

The contribution of transforming growth factor-β and epidermal growth factor signalling to airway remodelling in chronic asthma

Boxall

Holgate²,

Davies³

2006

Eur Respir J

226

187

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Asthma is increasing in prevalence in the developing world, affecting ,10% of the world's population. It is characterised by chronic lung inflammation and airway remodelling associated with wheezing, shortness of breath, acute bronchial hyperresponsiveness to a variety of innocuous stimuli and a more rapid decline in lung function over time.Airway remodelling, involving proliferation and differentiation of mesenchymal cells, particularly myofibroblasts and smooth muscle cells, is generally refractory to corticosteroids and makes a major contribution to disease chronicity. Transforming growth factor-b is a potent profibrogenic factor whose expression is increased in the asthmatic airways and is a prime candidate for the initiation and persistence of airway remodelling in asthma.This review highlights the role of transforming growth factor-b in the asthmatic lung, incorporating biosynthesis, signalling pathways and functional outcome. In vivo, however, it is the balance between transforming growth factor-b and other growth factors, such as epidermal growth factor, which will determine the extent of fibrosis in the airways.A fuller comprehension of the actions of transforming growth factor-b, and its interaction with other signalling pathways, such as the epidermal growth factor receptor signalling cascade, may enable development of therapies that control airway remodelling where there is an unmet clinical need.

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Tyrosine kinase inhibitors: a new approach for asthma

Cited by 82 publications

References 200 publications

Protein Flexibility and Ligand Rigidity: A Thermodynamic and Kinetic Study of ITAM‐Based Ligand Binding to Syk Tandem SH2

Protein Flexibility and Ligand Rigidity: A Thermodynamic and Kinetic Study of ITAM‐Based Ligand Binding to Syk Tandem SH2

Soy isoflavones and immunity

The contribution of transforming growth factor-β and epidermal growth factor signalling to airway remodelling in chronic asthma

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