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Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities

The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some succe...

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Detalles Bibliográficos
Autores principales: Blunt, Matthew D., Ward, Stephen G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410520/
https://www.ncbi.nlm.nih.gov/pubmed/22876243
http://dx.doi.org/10.3389/fimmu.2012.00226
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author Blunt, Matthew D.
Ward, Stephen G.
author_facet Blunt, Matthew D.
Ward, Stephen G.
author_sort Blunt, Matthew D.
collection PubMed
description The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P(3) at the D5 position of the inositol ring to create PI(3,4)P(2). In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system.
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spelling pubmed-34105202012-08-08 Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities Blunt, Matthew D. Ward, Stephen G. Front Immunol Immunology The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P(3) at the D5 position of the inositol ring to create PI(3,4)P(2). In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system. Frontiers Research Foundation 2012-08-02 /pmc/articles/PMC3410520/ /pubmed/22876243 http://dx.doi.org/10.3389/fimmu.2012.00226 Text en Copyright © 2012 Blunt and Ward. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
spellingShingle Immunology
Blunt, Matthew D.
Ward, Stephen G.
Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
title Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
title_full Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
title_fullStr Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
title_full_unstemmed Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
title_short Pharmacological Targeting of Phosphoinositide Lipid Kinases and Phosphatases in the Immune System: Success, Disappointment, and New Opportunities
title_sort pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410520/
https://www.ncbi.nlm.nih.gov/pubmed/22876243
http://dx.doi.org/10.3389/fimmu.2012.00226
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