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Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells
Open accessAbstract
Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation, and survival, pharmacologic inhibitors targeting components of the PI3K pathway are actively being developed as therapeutics for the treatment of inflammatory disorders and cancer. These targeted drugs inhibit the activity of either PI3K itself or downstream protein kinases. However, a previously unexplored, alternate strategy is to activate the negative regulatory phosphatases in this pathway. The SH2-containing inositol-5′-phosphatase SHIP1 is a normal physiologic counter-regulator of PI3K in immune/hematopoietic cells that hydrolyzes the PI3K product phosphatidylinositiol-3,4,5-trisphosphate (PIP3). We now describe the identification and characterization of potent and specific small-molecule activators of SHIP1. These compounds represent the first small-molecule activators of a phosphatase, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophage and mast cells. Mechanism of activation studies with these compounds suggest that they bind a previously undescribed, allosteric activation domain within SHIP1. Furthermore, in vivo administration of these compounds was protective in mouse models of endotoxemia and acute cutaneous anaphylaxis, suggesting that SHIP1 agonists could be used therapeutically to inhibit the PI3K pathway.
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Helgason, C. D., Damen, J. E., Rosten, P., Grewal, R., Sorensen, P., Chappel, S. M., Borowski, A., Jirik, F., Krystal, G., & Humphries, R. K. (1998) · Genes & Development · doi:10.1101/gad.12.11.1610 · Cited by 556
Self-citationCritical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation
Foukas, L. C., Claret, M., Pearce, W., Okkenhaug, K., Meek, S., Peskett, E., Sancho, S., Smith, A. J. H., Withers, D. J., & Vanhaesebroeck, B. (2006) · Nature · doi:10.1038/nature04694 · Cited by 463
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Allavena, P., Sica, A., Solinas, G., Porta, C., & Mantovani, A. (2008) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2007.07.004 · Cited by 1,044
Gewinner, C., Wang, Z. C., Richardson, A., Teruya-Feldstein, J., Etemadmoghadam, D., Bowtell, D., Barretina, J., Lin, W. M., Rameh, L., Salmena, L., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.06.006 · Cited by 461
Anaphylaxis: Lessons from mouse models
Finkelman, F. D. (2007) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2007.07.033 · Cited by 404
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Metadata
- Authors
- Ong, C. J., Ming-Lum, A., Nodwell, M., Ghanipour, A., Yang, L., Williams, D. E., Kim, J., Demirjian, L., Qasimi, P., Ruschmann, J., Cao, L.-P., Ma, K., Chung, S. W., Duronio, V., Andersen, R. J., Krystal, G., & Mui, A. L.-F.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-09-15
- Volume
- 110
- Issue
- 6
- Pages
- 1942-1949
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2051118426
- Cited by
- 158
- References
- 2
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- bronze
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- The paper
- Ong, C. J., Ming-Lum, A., Nodwell, M., Ghanipour, A., Yang, L., Williams, D. E., Kim, J., Demirjian, L., Qasimi, P., Ruschmann, J., Cao, L.-P., Ma, K., Chung, S. W., Duronio, V., Andersen, R. J., Krystal, G., & Mui, A. L.-F. (2007). Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood. https://doi.org/10.1182/blood-2007-03-079699
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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