Targeting phosphoinositide 3-kinase delta for allergic asthma

Wendy C. Rowan; Janet L. Smith; Karen Affleck; Augustin Amour

doi:10.1042/BST20110665

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Biochemical Society Transactions (2012) 40, (240–245) (Printed in Great Britain)

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Biochemical Society Focused Meeting

Targeting phosphoinositide 3-kinase δ for allergic asthma

Wendy C. Rowan*, Janet L. Smith†, Karen Affleck† and Augustin Amour‡¹

*Biological Reagents and Assay Development, Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., †Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K., and ‡Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Key words: allergic asthma, B-cell, cytokine, mast cell, phosphoinositide 3-kinase (PI3K), T-cell.

Abbreviations: BCR, B-cell receptor; BTK, Bruton's tyrosine kinase; FcϵRI, high-affinity IgE receptor; Foxo, forkhead box O; GEF, guanine-nucleotide-exchange factor; GPCR, G-protein-coupled receptor; IL, interleukin; ITK, IL-2-inducible T-cell kinase; NF-κB, nuclear factor κB; PDK1, phosphoinositide-dependent kinase 1; PH, pleckstrin homology; PI3K, phosphoinositide 3-kinase; TCR, T-cell receptor; T_reg, regulatory T-cell.

¹To whom correspondence should be addressed (email augustin.j.amour@gsk.com).

Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kδ inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kδ inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma.