title: Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells.
abstract: 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 (PIP(3)). 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.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, Canda.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
authors.forename: Andrew
authors.initials: A
authors.lastname: Ming-Lum
authors.forename: Matt
authors.initials: M
authors.lastname: Nodwell
authors.forename: Ali
authors.initials: A
authors.lastname: Ghanipour
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.forename: Loutfig
authors.initials: L
authors.lastname: Demirjian
authors.forename: Pooran
authors.initials: P
authors.lastname: Qasimi
authors.forename: Jens
authors.initials: J
authors.lastname: Ruschmann
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Cao
authors.forename: Kewei
authors.initials: K
authors.lastname: Ma
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Chung
authors.forename: Vincent
authors.initials: V
authors.lastname: Duronio
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
authors.forename: Alice L-F
authors.initials: AL
authors.lastname: Mui
mesh_terms: D000494:Allosteric Regulation; D000707:Anaphylaxis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D047468:Immunoprecipitation; D000072181:Inositol Polyphosphate 5-Phosphatases; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012882:Skin Tests
chemical_list: C544924:AQX MN100; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D018129:Phosphatidylinositol Phosphates; D011083:Polycyclic Compounds; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C414692:pelorol; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium