GNE-7056
GNE-7056 is an orally active interleukin-2-inducible T-cell kinase (ITK) inhibitor with a Ki of 0.2 nM against human kinase, and exhibits high selectivity over LCK kinase. GNE-7056 inhibits PLCγ-1 phosphorylation, suppresses the production of IL-2, IL-4, IL-13 and TH2 cytokines, reduces CD4+ T-cell proliferation, and inhibits activation-induced cell death of CD4+ T cells by decreasing the abundance of FasL. GNE-7056 can be used in asthma-related research.
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- CAS. Nr.: 1557236-81-3
- Formel: C25H31N5O2S
- Molecular Weight:465.61
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Speicherung:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Biologische Aktivität
Beschreibung
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ITK 0.2 nM (Ki) |
PLCγ-1 |
IL-2 |
IL-4 |
IL-13 |
In Vitro
GNE-7056 (compound 20) potently inhibits purified ITK enzyme with a Ki of 0.2 nM[1].
GNE-7056 inhibits TCR-stimulated PLCγ phosphorylation in Jurkat cells with an IC50 of 28 nM[1].
GNE-7056 inhibits TCR-mediated PLC-γ1 phosphorylation in Jurkat cells with an IC50 of 28 nM[2].
GNE-7056 (48 h) exhibits antiproliferative activity in unstimulated Jurkat cells with an IC50 of 30 μM[1].
GNE-7056 inhibits purified LCK enzyme with a Ki of 1.6 μM, demonstrating an 8000-fold selectivity for ITK over LCK[1].
GNE-7056 has a kinetic solubility of 45 μM in pH 7.4 aqueous phosphate buffer[1].
GNE-7056 (0.1 μM) inhibits 10 out of 285 kinases by >70% at 0.1 μM, demonstrating broad kinase selectivity[1].
GNE-7056 (10 μM) inhibits hERG channel activity by 3.6% at 10 μM[1].
GNE-7056 exhibits antiproliferative activity in human hepatocytes with an IC50 of 83 μM[1].
GNE-7056 potently inhibits recombinant ITK enzyme with a Ki of 0.2 nM[2].
GNE-7056 (1.3-8333 nM; 45 min pre-stimulation, 2 min phosphorylation stimulation, overnight cytokine stimulation) inhibits TCR-mediated IL-2 and IL-13 production, as well as PLC-γ1 phosphorylation, in polarized human TH2 cells with IC50 values of 32 nM and 126 nM, respectively, without reducing cell viability[2].
GNE-7056 (0.57-20000 nM; 45 min pre-stimulation, 2 min phosphorylation stimulation, overnight cytokine and viability stimulation) inhibits TCR-mediated production of IL-2, IL-4, IL-5, and IL-13, as well as PLC-γ1 phosphorylation, in polarized mouse TH2 cells with IC50 values ranging from 23 nM to 325 nM, and reduces cell viability with a much higher IC50 of 2068 nM[2].
GNE-7056 (167-1500 nM; 16 hours) dose-dependently inhibits AICD in activated mouse OT-II CD4+ T cells by reducing cell surface FasL abundance, acting through a Fas-dependent pathway[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:polarized mouse TH2 cells
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Concentration:0.42-20000 nM
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Incubation Time:45 min pre-stimulation, 2 min phosphorylation stimulation, overnight cytokine and viability stimulation
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Result:Inhibited the TCR-mediated production of IL-2, IL-4, IL-5, and IL-13 in TH2 cells of polarized mice, as well as the phosphorylation of PLC-γ1.
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Cell Line:activated mouse OT-II CD4+ T cells
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Concentration:167-1500 nM
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Incubation Time:16 hours
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Result:Reduced the percentage of apoptotic OT-II cells in a dose-dependent manner.
Decreased cell surface abundance of FasL in a dose-dependent fashion.
Had anti-apoptotic effect blocked by anti-FasL antibody, indicating a Fas-dependent mechanism.
In Vivo
GNE-7056 (100 mg/kg; p.o.; twice daily; 3 days) suppresses the proliferation of CD4+ T cells and reduces IL-4 production to 17.8% of the CD4+ KJ126+ population in a mouse TH2 immunization model[2].
GNE-7056 (5-100 mg/kg; p.o.; twice daily; days 35 to 41) exacerbates airway hyperresponsiveness and increases TH2-type cytokine production and lymphoid hyperplasia in a mouse OVA-induced asthma model treated during antigen challenge[2].
GNE-7056 (100 mg/kg; p.o.; twice daily; days 35 to 41) selectively exacerbates TH2-type cytokine production and lymphoid hyperplasia in wild-type mice, but not Itk-/- mice, confirming on-target ITK inhibition effects in an OVA-induced asthma model[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57Bl/6 (female, 6-8 weeks old, T-cell receptor-mediated cytokine release model via anti-CD3 antibody 145-2C11 challenge)[1]
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Dosage:10 mg/kg; 30 mg/kg; 100 mg/kg; 200 mg/kg
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Administration:i.p.; single dose
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Result:Reduced serum IL-2 levels by 55% and serum IL-13 levels by 62%.
Reduced serum IL-2 levels by 90% and serum IL-13 levels by 95%.
Reduced serum IL-2 levels by 98%.
Reduced serum IL-2 levels by 98% and serum IL-13 levels by 100%.
Reached ~80 μM plasma concentration at 2.5 hours post-dosing with the 200 mg/kg dose.
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Animal Model:BALB/c mice (6- to 10-week-old female; DO11.10 TCR/IL-4-GFP splenocyte transfer, followed by subcutaneous immunization with OVA protein plus papain adjuvant)[2]
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Dosage:100 mg/kg
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Administration:p.o.; twice daily; 3 days
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Result:Reduced total DLN cell count, absolute number of CD4+ KJ126+ cells, and number of IL-4-producing (GFP+) CD4+ KJ126+ cells in DLNs.
Reduced the percentage of IL-4-expressing cells within the CD4+ KJ126+ population to 17.8%.
Minimally changed the percentage of CD4+ KJ126+ cells in DLNs (0.50% versus 0.54% in vehicle-treated mice).
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Animal Model:BALB/c mice (7- to 8-week-old female; intraperitoneal immunization with TNP-OVA plus aluminum hydroxide adjuvant, followed by aerosol challenge with 1% TNP-OVA)[2]
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Dosage:5 mg/kg; 25 mg/kg; 100 mg/kg
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Administration:p.o.; twice daily; days 35 to 41
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Result:Exacerbated airway hyperresponsiveness.
Failed to reduce lung inflammation severity or goblet cell hyperplasia.
Increased total cell, eosinophil, and lymphocyte counts in BALF.
Increased concentrations of TH2-type cytokines (IL-4, IL-5, IL-13) in BALF.
Did not increase the percentage of cytokine-producing CD4+ T cells in the lung on a per-cell basis.
Increased total mediastinal DLN cell count and CD4+ T cell count.
Reduced apoptosis (measured as cleaved caspase-3 staining area) in mesenteric lymph nodes.
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Animal Model:C57BL/6 wild-type and Itk-/- littermate mice (intraperitoneal immunization with TNP-OVA plus aluminum hydroxide adjuvant, followed by aerosol challenge with 1% TNP-OVA)[2]
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Dosage:100 mg/kg
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Administration:p.o.; twice daily; days 35 to 41
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Result:Increased TH2-type cytokine concentrations (IL-5, IL-13) in BALF, total mediastinal DLN cell count, and CD4+ T cell count in wild-type mice, but had no such effects in Itk-/- mice.
Reduced apoptosis (measured as cleaved caspase-3 staining area) in mesenteric lymph nodes of wild-type mice but not Itk-/- mice.
Chemical Information
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CAS. Nr. 1557236-81-3
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Molecular Weight 465.61
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Formel C25H31N5O2S
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SMILES
O=C(C1=NNC2=C1CCC(C)(C2)C)NC3=CN(C(C4CCS(CC4)=O)C5=CC=CC=C5)N=C3
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
Reinheit & Dokumentation
Verweise
Calculators
Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
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