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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.
Br J Pharmacol. 2013 Mar; 168(6):1506-18.BJ

Abstract

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.

Authors+Show Affiliations

Aquinox Pharmaceuticals Inc., Richmond, BC, Canada. gstenton@aqxpharma.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23121445

Citation

Stenton, Grant R., et al. "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, vol. 168, no. 6, 2013, pp. 1506-18.
Stenton GR, Mackenzie LF, Tam P, et al. 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. Br J Pharmacol. 2013;168(6):1506-18.
Stenton, G. R., Mackenzie, L. F., Tam, P., Cross, J. L., Harwig, C., Raymond, J., Toews, J., Wu, J., Ogden, N., MacRury, T., & Szabo, C. (2013). 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, 168(6), 1506-18. https://doi.org/10.1111/bph.12039
Stenton GR, et al. 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. Br J Pharmacol. 2013;168(6):1506-18. PubMed PMID: 23121445.
* Article titles in AMA citation format should be in sentence-case
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 -