Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells

• Published in: Blood Vol. 110; no. 6; pp. 1942 - 1949
• Main Authors: Ong, Christopher J., Ming-Lum, Andrew, Nodwell, Matt, Ghanipour, Ali, Yang, Lu, Williams, David E., Kim, Joseph, Demirjian, Loutfig, Qasimi, Pooran, Ruschmann, Jens, Cao, Li-Ping, Ma, Kewei, Chung, Stephen W., Duronio, Vincent, Andersen, Raymond J., Krystal, Gerald, Mui, Alice L.-F.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.09.2007; The Americain Society of Hematology
• Subjects: Allosteric Regulation; Anaphylaxis - drug therapy; Anaphylaxis - metabolism; Anaphylaxis - pathology; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Calcium - metabolism; Cells, Cultured; Endotoxemia - drug therapy; Endotoxemia - metabolism; Endotoxemia - pathology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Enzymologic; Humans; Immunoprecipitation; Inositol Polyphosphate 5-Phosphatases; Kidney - cytology; Kidney - metabolism; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mast Cells - drug effects; Mast Cells - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - metabolism; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation - drug effects; Polycyclic Compounds - chemistry; Polycyclic Compounds - pharmacology; Porifera - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Sesquiterpenes - chemistry; Sesquiterpenes - pharmacology; Signal Transduction - drug effects; Skin Tests; Agonist; Enzyme; Transferases; Phosphatidyl-3,4,5-triphosphate 5-phosphatase 1; Rodentia; Antiinflammatory agent; Hematopoietic cell; In vitro; Biological activity; 1-Phosphatidylinositol 3-kinase; Prevention; Vertebrata; Mammalia; Immunology; Treatment; Mouse; Animal; Passive cutaneous anaphylaxis; Inhibitor; Mast cell; Endotoxemia; Macrophage
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-03-079699

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.