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Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities

Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities
Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities
The predominant expression of the ? and ? 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 PI3K? inhibitors, progress in developing selective inhibitors of PI3K? 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)P3 at the D5 position of the inositol ring to create PI(3,4)P2. 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.
1664-3224
1-15
Blunt, Matthew D.
b1109de3-6045-4bc3-bd77-6cf26504697d
Ward, Stephen G.
055fb146-f745-4b52-abf5-10d9de7e1673
Blunt, Matthew D.
b1109de3-6045-4bc3-bd77-6cf26504697d
Ward, Stephen G.
055fb146-f745-4b52-abf5-10d9de7e1673

Blunt, Matthew D. and Ward, Stephen G. (2012) Pharmacological targeting of phosphoinositide lipid kinases and phosphatases in the immune system: success, disappointment, and new opportunities. Frontiers in Immunology, 3, 1-15. (doi:10.3389/fimmu.2012.00226). (PMID:22876243)

Record type: Article

Abstract

The predominant expression of the ? and ? 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 PI3K? inhibitors, progress in developing selective inhibitors of PI3K? 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)P3 at the D5 position of the inositol ring to create PI(3,4)P2. 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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Published date: 2 August 2012
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 392718
URI: https://eprints.soton.ac.uk/id/eprint/392718
ISSN: 1664-3224
PURE UUID: ff08c546-b160-4087-87c3-74f7de551cf3

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Date deposited: 14 Apr 2016 14:19
Last modified: 19 Jul 2019 20:09

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Author: Stephen G. Ward

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