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Review ArticleReview Article

Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies

John G. Foster, Matthew D. Blunt, Edward Carter and Stephen G. Ward
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews October 2012, 64 (4) 1027-1054; DOI: https://doi.org/10.1124/pr.110.004051
John G. Foster
Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom
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Matthew D. Blunt
Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom
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Edward Carter
Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom
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Stephen G. Ward
Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom
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David R. Sibley
Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, United Kingdom
Roles: ASSOCIATE EDITOR
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Abstract

The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractive targets for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.

Footnotes

  • This article is available online at http://pharmrev.aspetjournals.org.

    http://dx.doi.org/10.1124/pr.110.004051.

  • © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 64 (4)
Pharmacological Reviews
Vol. 64, Issue 4
1 Oct 2012
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Review ArticleReview Article

INHIBITION OF PI3K IN THE IMMUNE SYSTEM

John G. Foster, Matthew D. Blunt, Edward Carter and Stephen G. Ward
Pharmacological Reviews October 1, 2012, 64 (4) 1027-1054; DOI: https://doi.org/10.1124/pr.110.004051

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Review ArticleReview Article

INHIBITION OF PI3K IN THE IMMUNE SYSTEM

John G. Foster, Matthew D. Blunt, Edward Carter and Stephen G. Ward
Pharmacological Reviews October 1, 2012, 64 (4) 1027-1054; DOI: https://doi.org/10.1124/pr.110.004051
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  • Article
    • Abstract
    • I. Introduction
    • II. Phosphoinositide 3-Kinase Signaling Pathway
    • III. Role of Phosphoinositide 3-Kinases γ and δ in the Immune System
    • IV. Cooperation between Phosphoinositide 3-Kinase Isoforms in the Immune Response
    • V. Emergence of Chemical Tools to Target Phosphoinositide 3-Kinase Signaling
    • VI. Development of Phosphoinositide 3-Kinase Inhibitors with Which to Target the Immune System
    • VII. Therapeutic Potential of Inhibitors Targeting Phosphoinositide 3-Kinase γ and δ For Immune Disorders
    • VIII. Beyond the Class I Phosphoinositide 3-Kinase Isoforms: Increased Understanding of a Role for Class II and III Phosphoinositide 3-Kinases in the Immune System
    • IX. SH2-Domain Containing Inositol-5-phosphatase-1: An Alternative Target for Selective Modulation of Phosphoinositide 3-Kinase in the Immune System
    • X. Manipulation of SH2-Domain Containing Inositol-5-phosphatase-1 Catalytic Activity with Small Molecules
    • XI. Conclusions
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • References
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