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

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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. Linked Article This article is accompanied by Stenton et al., pp. 1519-1529 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12038

Original languageEnglish (US)
Pages (from-to)1506-1518
Number of pages13
JournalBritish Journal of Pharmacology
Volume168
Issue number6
DOIs
StatePublished - Mar 2013
Externally publishedYes

Fingerprint

Chemotaxis
Pharmacokinetics
Leukocyte Chemotaxis
Phosphorylation
Mast Cells
Inositol Polyphosphate 5-Phosphatases
In Vitro Techniques
4-(4-(aminomethyl)-7a-methyl-1-methylideneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol
Cytokines
Inflammation
Hexosaminidases
Enzyme Assays
Human Activities
Biological Availability
Lung Diseases
Half-Life
Pharmacology
Dogs
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

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

In: British Journal of Pharmacology, Vol. 168, No. 6, 03.2013, p. 1506-1518.

Research output: Contribution to journalArticle

Stenton, Grant R. ; MacKenzie, Lloyd F. ; Tam, Patrick ; Harwig, Curtis ; Raymond, Jeffrey ; Toews, Judy ; Wu, Joyce ; Ogden, Nancy ; MacRury, Thomas ; Szabo, Csaba. / 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. In: British Journal of Pharmacology. 2013 ; Vol. 168, No. 6. pp. 1506-1518.
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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. Linked Article This article is accompanied by Stenton et al., pp. 1519-1529 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12038",
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AU - Stenton, Grant R.

AU - MacKenzie, Lloyd F.

AU - Tam, Patrick

AU - Harwig, Curtis

AU - Raymond, Jeffrey

AU - Toews, Judy

AU - Wu, Joyce

AU - Ogden, Nancy

AU - MacRury, Thomas

AU - Szabo, Csaba

PY - 2013/3

Y1 - 2013/3

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. Linked Article This article is accompanied by Stenton et al., pp. 1519-1529 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12038

AB - 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. Linked Article This article is accompanied by Stenton et al., pp. 1519-1529 of this issue. To view this article visit http://dx.doi.org/10.1111/bph.12038

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KW - PI3K

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