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    Entospletinib (GS9973)
    Entospletinib (GS9973)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0655
    CAS #: 1229208-44-9Purity ≥98%

    Description: Entospletinib (formerly known as GS-9973) is a novel, potent, orally bioavailable, and highly selective Syk inhibitor with potential anti-inflammatory and immunomodulatory activities. It inhibits Syk with an IC50 of 7.7 nM in a cell-free assay. Entospletinib displayed high in vivo anti-inflammatory activity in Rat Collagen-Induced Arthritis (CIA) Model. In monocytes, GS-9973 inhibited immune-complex-stimulated cytokine production and BCR-mediated proliferation and activation of B-cells. In chronic lymphocytic leukemia (CLL) cells, GS-9973 significantly reduced pAkt and ribosomal S6 phosphorylation.  These results suggested that GS-9973 inhibited B-cell receptor (BCR) mediated signaling pathways.

    References: J Med Chem. 2014 May 8;57(9):3856-73; Oncotarget. 2014 Feb 28;5(4):908-15.

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    Molecular Weight (MW)411.46
    FormulaC23H21N7O
    CAS No.1229208-44-9
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 82 mg/mL (199.3 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)4% DMSO+30% PEG 300+5% Tween 80+ddH2O: 2.5 mg/mL
    SynonymsGS-9973; Entospletinib; GS9973; GS 9973; 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine 

    InChi Key: XSMSNFMDVXXHGJ-UHFFFAOYSA-N

    InChi Code: InChI=1S/C23H21N7O/c1-2-17-14-25-28-20(17)13-16(1)21-15-30-8-7-24-23(30)22(27-21)26-18-3-5-19(6-4-18)29-9-11-31-12-10-29/h1-8,13-15H,9-12H2,(H,25,28)(H,26,27)

    SMILES Code: C12=NC=CN1C=C(C3=CC4=C(C=C3)C=NN4)N=C2NC5=CC=C(N6CCOCC6)C=C5


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    In Vitro

    In vitro activity: GS-9973 shows good bidirectional permeability across Caco-2 cell monolayers in vitro. In cells, GS-9973 also shows excellent selectivity for Syk, and potently inhibits BCR-mediated activation and proliferation of B-cells as well as immune-complex-stimulated cytokine production in monocytes. The combination of idelalisib and GS-9973 synergistically inhibits CLL cell viability and further disrupts chemokine signaling.


    Kinase Assay: Full-length baculovirus-expressed Syk kinase activity is measured in a Lance-based assay format in a final volume of 25 μL containing 25 mM Tris–HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na3VO4, 10 mM MgCl2, 0.5 μM Promega PTK biotinylated peptide substrate 1, 0.01% casein, 0.01% Triton X-100, 0.25% glycerol, and 40 mM ATP (Km for ATP) incubated at room temperature for 60 min. Reactions are stopped with the addition of 30 mM EDTA containing 30 μL of SA-APC and 4 nM PT-66 antibody and the plates measured on a Perkin-Elmer Envision. IC50 values for test compounds are determined using a four-parameter linear regression algorithm.


    Cell Assay: Functional impact on cellular Flt3 activity is determined by measuring compound inhibition of MV-4-11 cell proliferation. A total of 104 cells are diluted in RPMI medium containing 10% FBS in 96-well flat-bottomed tissue culture plates and incubated with compound dilutions for 72 h at 37 °C. Alamar blue (10%) is added to the cells, which were incubated for an additional 12-18 h at 37 °C, and inhibition of the relative cell numbers is determined by spectrophotometer readings at 570/600 nm.

    In VivoGS-9973 (1 mg/kg p.o.) shows moderate to high bioavailability in rat and dog. In a rat collagen-induced arthritis model, GS-9973 (1-10 mg/kg p.o.) significantly inhibits ankle inflammation. Moreover, GS-9973 also shows disease-modifying activity in multiple histological measurements, including inhibition of pannus formation, cartilage damage, bone resorption, and peritosteal bone formation with ED50 ranging from 1.2 to 3.9 mg/kg.
    Animal modelRat Collagen-Induced Arthritis (CIA) Model
    Formulation & DosageDissolved in Cremophor/ethanol/saline;10 mg/kg; oral administration
    References

    J Med Chem. 2014 May 8;57(9):3856-73; Oncotarget. 2014 Feb 28;5(4):908-15.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Entospletinib (GS-9973)

    Treatment of primary CLL cells (n =14) co-cultured with HS5 stromal cells with idelalisib (100 nM) or GS-9973 (100 nM), alone or in combination (100 nM each), results in decreased AKT phosphorylation. Oncotarget. 2014 Feb 28;5(4):908-15.


    Entospletinib (GS-9973)

    Disease status and biologic CLL disease characteristics. Oncotarget. 2014 Feb 28;5(4):908-15.


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