TY - JOUR T1 - 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. AU - Stenton,Grant R, AU - Mackenzie,Lloyd F, AU - Tam,Patrick, AU - Cross,Jennifer L, AU - Harwig,Curtis, AU - Raymond,Jeffrey, AU - Toews,Judy, AU - Wu,Joyce, AU - Ogden,Nancy, AU - MacRury,Thomas, AU - Szabo,Csaba, PY - 2012/03/22/received PY - 2012/09/14/revised PY - 2012/10/16/accepted PY - 2012/11/6/entrez PY - 2012/11/6/pubmed PY - 2013/8/24/medline SP - 1506 EP - 18 JF - British journal of pharmacology JO - Br J Pharmacol VL - 168 IS - 6 N2 - BACKGROUND: The SH2-containing inositol-5'-phosphatase 1 (SHIP1) metabolizes PI(3,4,5)P3 to PI(3,4)P2. SHIP1-deficient mice exhibit progressive inflammation. Pharmacological activation of SHIP1 is emerging as a potential therapy for pulmonary inflammatory diseases. Here we characterize the efficacy of AQX-1125, a small-molecule SHIP1 activator currently in clinical development. EXPERIMENTAL APPROACH: The effects of AQX-1125 were tested in several in vitro assays: on enzyme catalytic activity utilizing recombinant human SHIP1, on Akt phosphorylation in SHIP1-proficient and SHIP1-deficient cell lines, on cytokine release in murine splenocytes, on human leukocyte chemotaxis using modified Boyden chambers and on β-hexosaminidase release from murine mast cells. In addition, pharmacokinetic and drug distribution studies were performed in rats and dogs. RESULTS: AQX-1125 increased the catalytic activity of human recombinant SHIP1, an effect, which was absent after deletion of the C2 region. AQX-1125 inhibited Akt phosphorylation in SHIP1-proficient but not in SHIP1-deficient cells, reduced cytokine production in splenocytes, inhibited the activation of mast cells and inhibited human leukocyte chemotaxis. In vivo, AQX-1125 exhibited >80% oral bioavailability and >5 h terminal half-life. CONCLUSIONS: Consistent with the role of SHIP1 in cell activation and chemotaxis, the SHIP1 activator AQX-1125 inhibits Akt phosphorylation, inflammatory mediator production and leukocyte chemotaxis in vitro. The in vitro effects and the pharmacokinetic properties of the compound make it a suitable candidate for in vivo testing in various models of inflammation. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/23121445/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_ L2 - https://doi.org/10.1111/bph.12039 DB - PRIME DP - Unbound Medicine ER -