Characterization of AQX-1125, a small-molecule SHIP1 activator Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo

British Journal of Pharmacology

Volumn 168, Issue 6, 2013, Pages 1506-1518

  Stenton, Grant R ^a   MacKenzie, Lloyd F ^a   Tam, Patrick ^a   Harwig, Curtis ^a   Raymond, Jeffrey ^a   Toews, Judy ^a   Wu, Joyce ^a   Ogden, Nancy ^a   MacRury, Thomas ^a   Szabo, Csaba ^a  

^a Aquinox Pharmaceuticals Inc   (Canada)

Author keywords

cell motility; chemotaxis; inflammation; phosphatidylinositol; PI3K; pulmonary; SHIP1

Indexed keywords

ANTIINFLAMMATORY AGENT; AQX 1125; AQX MN 115; BETA N ACETYLHEXOSAMINIDASE; PHOSPHATASE; PROTEIN KINASE B; RECOMBINANT PROTEIN; RECOMBINANT SH2 CONTAINING INOSITOL 5' PHOSPHATASE 1; SH2 CONTAINING INOSITOL 5' PHOSPHATASE 1; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CELL ACTIVATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RELEASE; DOG; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DETERMINATION; DRUG DISTRIBUTION; DRUG EFFECT; DRUG EFFICACY; DRUG HALF LIFE; DRUG PROTEIN BINDING; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME KINETICS; ENZYME RELEASE; FEMALE; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LEUKEMIA CELL LINE; LEUKOCYTE; LIPOPHILICITY; MALE; MAST CELL; MAXIMUM PLASMA CONCENTRATION; MONONUCLEAR CELL; MOUSE; NEUTROPHIL CHEMOTAXIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RAT; SINGLE DRUG DOSE; SPLEEN CELL; TIME TO MAXIMUM PLASMA CONCENTRATION; TISSUE LEVEL;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CELL LINE; CELLS, CULTURED; CHEMOTAXIS, LEUKOCYTE; CYCLOHEXANOLS; DOGS; ENZYME ACTIVATORS; FEMALE; HUMANS; INDANS; ISOENZYMES; MALE; MAST CELLS; MICE; MICE, INBRED C57BL; PHOSPHORIC MONOESTER HYDROLASES; PHOSPHORYLATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTO-ONCOGENE PROTEINS C-AKT; RATS; RATS, SPRAGUE-DAWLEY; RECOMBINANT PROTEINS; SPLEEN;

EID: 84874408370     PISSN: 00071188     EISSN: 14765381     Source Type: Journal    
DOI: 10.1111/bph.12039     Document Type: Article

References (36)

1. Andersen R, Nodwell M, Mui A, (2007). SHIP1 modulator compounds. WO 2007/147251 A1.
2. Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB, (2003). The inositol 5′-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity. J Biol Chem 278: 38628-38636.
3. Brooks R, Fuhler GM, Iyer S, Smith MJ, Park MY, Paraiso KHT, et al. (2010). SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. J Immunol 184: 3582-3589.
4. Conde C, Gloire G, Piette J, (2011). Enzymatic and non-enzymatic activities of SHIP-1 in signal transduction. Biochem Pharmacol 10: 1320-1334.
5. Freeburn RW, Wright KL, Burgess SJ, Astoul E, Cantrell DA, Ward SG, (2002). Evidence that SHIP-1 contributes to phosphatidylinositol 3,4,5-trisphosphate metabolism in T lymphocytes and can regulate novel phosphoinositide 3-kinase effectors. J Immunol 169: 5441-5450.
6. Gabhann JN, Higgs R, Brennan K, Thomas W, Damen JE, Ben Larbi N, et al. (2010). Absence of SHIP-1 results in constitutive phosphorylation of tank-binding kinase 1 and enhanced TLR3-dependent IFN-beta production. J Immunol 184: 2314-2320.
7. Haddon DJ, Antignano F, Hughes MR, Blanchet MR, Zbytnuik L, Krystal G, et al. (2009). SHIP1 is a repressor of mast cell hyperplasia, cytokine production, and allergic inflammation in vivo. J Immunol 183: 228-236.
8. Harris SJ, Parry RV, Foster JG, Blunt MD, Wang A, Marelli-Berg F, et al. (2011). Evidence that the lipid phosphatase SHIP-1 regulates T lymphocyte morphology and motility. J Immunol 186: 4936-4945.
9. Horn S, Endl E, Fehse B, Weck MM, Mayr GW, Jücker M, (2004). Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle. Leukemia 18: 1839-1849.
10. Keck S, Freudenberg M, Huber M, (2010). Activation of murine macrophages via TLR2 and TLR4 is negatively regulated by a Lyn/P13K module and promotedby SHIP1. J Immunol 184: 5809-5818.
11. Kerr WG, (2011). Inhibitor and activator: dual functions for SHIP in immunity and cancer. Ann N Y Acad Sci 1217: 1-17.
12. Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG, (2010). NC3Rs Reporting Guidelines Working Group. Br J Pharmacol 160: 1577-1579.
13. Kim CH, Hangoc G, Cooper S, Helgason CD, Yew S, Humphries RK, et al. (1999). Altered responsiveness to chemokines due to targeted disruption of SHIP. J Clin Invest 104: 1751-1759.
14. Krystal G, (2000). Lipid phosphatases in the immune system. Semin Immunol 12: 397-403.
15. Lesourne R, Fridman WH, Daëron M, (2005). Dynamic interactions of Fc gamma receptor IIB with filamin-bound SHIP1 amplify filamentous actin-dependent negative regulation of Fc epsilon receptor I signaling. J Immunol 174: 1365-1373.
16. Liu C, Miller H, Hui KL, Grooman B, Bolland S, Upadhyaya A, et al. (2011). A balance of Bruton's tyrosine kinase and SHIP activation regulates B cell receptor cluster formation by controlling actin remodeling. J Immunol 187: 230-239.
17. Liu Q, Sasaki T, Kozieradzki I, Wakeham A, Itie A, Dumont DJ, et al. (1999). SHIP1 is a negative regulator of growth factor receptor mediated PKB/Akt activation and myeloid cell survival. Genes Dev 13: 786-791.
18. Liu X, Hefesha H, Tanaka H, Scriba G, Fahr A, (2008). Lipophilicity measurement of drugs by reversed phase HPLC over wide pH range using an alkaline-resistant silica-based stationary phase, XBridgeTM Shield RP18. Chem Pharm Bull 56: 1417-1422.
19. Logan MR, Mandato CA, (2006). Regulation of the actin cytoskeleton by PIP2 in cytokinesis. Biol Cell 98: 377-388.
20. Ma K, Cheung SM, Marshall AJ, Duronio V, (2008). PI(3,4,5)P3 and PI(3,4)P2 levels correlate with PKB/akt phosphorylation at Thr308 and Ser473, respectively; PI(3,4)P2 levels determine PKB activity. Cell Signal 20: 684-694.
21. McGrath J, Drummond G, McLachlan E, Kilkenny C, Wainwright C, (2010). Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br J Pharmacol 160: 1573-1576.
22. Mancini A, Koch A, Wilms R, Tamura T, (2002). The SH2-containing inositol 5-phosphatase (SHIP)-1 is implicated in the control of cell-cell junction and induces dissociation and dispersion of MDCK cells. Oncogene 21: 1477-1484.
23. March ME, Ravichandran K, (2002). Regulation of the immune response by SHIP. Semin Immunol 14: 37-47.
24. Naal RMZG, Tabb J, Holowka D, Baird B, (2004). In situ measurement of degranulation as a biosensor based on RBL-2H3 mast cells. Biosens Bioelectron 20: 791-796.
25. Nishio M, Watanabe K, Sasaki J, Taya C, Takasuga S, Iizuka R, et al. (2007). Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1. Nat Cell Biol 9: 36-44.
26. Ong CJ, Ming-Lum A, Nodwell M, Ghanipour A, Yang L, Williams DE, et al. (2007). Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 110: 1942-1949.
27. Ooms LM, Horan KA, Rahman P, Seaton G, Gurung R, Kethesparan DS, et al. (2009). The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419: 29-49.
28. Parry RV, Harris SJ, Ward SG, (2010). Fine tuning T lymphocytes: a role for the lipid phosphatase SHIP-1. Biochim Biophys Acta 1804: 592-597.
29. Rahman P, Huysmans RD, Wiradjaja F, Gurung R, Ooms LM, Sheffield DA, et al. (2011). Silencer of Death Domains (SODD) inhibits skeletal muscle and Kidney Enriched Inositol 5-Phosphatase (SKIP) and regulates phosphoinositide 3-kinase (PI3K)/Akt signaling to the actin cytoskeleton. J Biol Chem 286: 29758-29770.
30. Raymond JR, Han K, Zhou Y, He Y, Noren B, Yee JGK, (2011). Indene derivatives as pharmaceutical agents. EP 2 277 848 A1.
31. Roehm NW, Rodgers GH, Hatfield SM, Glasebrook AL, (1991). An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. J Immunol Methods 142: 257-265.
32. Sasaki J, Kofuji S, Itoh R, Momiyama T, Takayama K, Murakami H, et al. (2010). The PtdIns(3,4)P2 phosphatase INPP4A is a suppressor of excitotoxic neuronal death. Nature 465: 497-501.
33. Sattler M, Verma S, Pride YB, Salgia R, Rohrschneider LR, Griffin JD, (2001). SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL. J Biol Chem 276: 2451-2458.
34. Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, et al. (2012). Characterization of AQX-1125, a small molecule SHIP1 activator. Part 2. Efficacy studies in pulmonary inflammation models in vivo. Br J Pharmacol 168: 1519-1529.
35. Wain CM, Westwick J, Ward SG, (2005). Heterologous regulation of chemokine receptor signaling by the lipid phosphatase SHIP in lymphocytes. Cell Signal 17: 1194-1202.
36. Yang L, Williams DE, Mui A, Ong C, Krystal G, van, Soest R, et al. (2005). Synthesis of pelorol and analogues: activators of the inositol 5-phosphatase SHIP. Org Lett 7: 1073-1076.