Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells.
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.
Ong
Christopher J
CJ
Department of Surgery, University of British Columbia, Vancouver, Canda.
Ming-Lum
Andrew
A
Nodwell
Matt
M
Ghanipour
Ali
A
Yang
Lu
L
Williams
David E
DE
Kim
Joseph
J
Demirjian
Loutfig
L
Qasimi
Pooran
P
Ruschmann
Jens
J
Cao
Li-Ping
LP
Ma
Kewei
K
Chung
Stephen W
SW
Duronio
Vincent
V
Andersen
Raymond J
RJ
Krystal
Gerald
G
Mui
Alice L-F
AL
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
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