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    Decernotinib (VX-509; VRT-831509; adelatinib)
    Decernotinib (VX-509; VRT-831509; adelatinib)

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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 #: V0320
    CAS #: 944842-54-0Purity ≥98%

    Description: Decernotinib (VX509; VRT831509; adelatinib) is a novel, potent, selective, and orally bioavailable inhibitor of JAK3 (Janus associated kinase) with potential anti-inflammatory activities. It inhibits JAK3, JAK1, JAK2, and TYK2 with Ki values of  2.5, 11, 13 and 11 nM, respectively. It has >4-fold selectivity for JAK3 over JAK1, JAK2, and TYK2. Decernotinib is being developed by Vertex for the treatment of inflammatory diseases such as rheumatoid arthritis-RA. In immune-mediated diseases, JAK3 is an essential component of the immune signaling cascade. This cascade ultimately contributes to abnormal immune response that results in chronic inflammation and, in the case of rheumatoid arthritis (RA).

    References: J Pharmacol Exp Ther. 2015 May;353(2):405-14; J Med Chem. 2015 Sep 24;58(18):7195-216.

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    Molecular Weight (MW)392.38
    FormulaC18H19F3N6O
    CAS No.944842-54-0
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 78 mg/mL (198.8 mM)
    Water: <1 mg/mL
    Ethanol: 20 mg/mL warmed (51.0 mM)
    SMILES CodeCC[[email protected]](NC1=NC(C2=CNC3=NC=CC=C32)=NC=C1)(C)C(NCC(F)(F)F)=O.
    Synonyms

    PubChem CID 59422203; VX-509; VRT831509 ; VRT-831509; VX509; VX 509 ; VRT 831509 ; Decernotinib; Adelatinib

    Chemical Name: (R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide


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    In Vitro

    In vitro activity: In HT-2 cells, Decernotinib inhibits IL-2–stimulated HT-2 STAT-5 phosphorylation, human T-cell blast proliferation, and CD40L/IL-4–induced B-cell proliferation.


    Kinase Assay: The effect of VX-509 on JAK3 activity is assessed by measuring the residual kinase activity of the recombinantly expressed JAK3 kinase domain using a radiometric assay. The final concentrations of the components in the assay are as follows: 100 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM dithiothreitol (DTT), 0.01% BSA, 0.25 nM JAK3, 0.25 mg/ml polyE4Y, and 5 μM 33P-γ-ATP (200 µCi/µmol). A 10 mM stock solution of VX-509 is prepared in DMSO, from which additional dilutions are prepared. A substrate mixture (100 mM HEPES, 10 mM MgCl2, 0.5 mg/ml polyE4Y, and 10 μM 33P-γ-ATP) is added and mixed with VX-509 stock solution. The reaction is initiated by the addition of an enzyme mixture [100 mM HEPES (pH 7.5), 10 mM MgCl2, 2 mM DTT, 0.02% BSA, 0.5 nM JAK3]. After 15 minutes, the reaction was quenched with 20% trichloroacetic acid (TCA). The quenched reaction was transferred to the GF/B filter plates and washed three times with 5% TCA. Following the addition of Ultimate Gold scintillant (50 μl), the samples were counted in a Packard TopCount gamma counter (PerkinElmer). In this procedure, the radioactivity trapped is a measure of the residual JAK3 kinase activity. From the activity versus concentration of VX-509 titration curve, the Ki value was determined by fitting the data to an equation for competitive tight binding inhibition kinetics using Prism software. 


    Cell Assay: Frozen purified human B cells atr thawed, washed, and resuspended in complete medium. Cells are plated onto a 96-well plate at a density of 2 × 105 cells/well. VX-509 is added, and plates are incubated for 30 minutes at 37°C, followed by stimulation with a combination of 10 ng/ml IL-4 and 1 μg/ml CD40L. DMSO alone is added to the top two rows, one of which is stimulated with IL-4 or CD40L (negative control) and the other of which served as a proliferation control. The plates are incubated at 37°C for 6 days. On day 6, cells are pulsed with [3H]thymidine for 7 hours and harvested onto filters for radioactive determination using a PerkinElmer-Wallace beta counter (1205 Betaplate Beta Liquid Scintillation Counter). Data are analyzed with Softmax pro software to generate an IC50 value.

    In VivoIn a rat model of collagen-induced arthritis, VX-509 (50 mg/kg, p.o.) results in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores. In a mouse model of oxazolone-induced delayed-type hypersensitivity, VX-509 (50 mg/kg, p.o.) significantly suppresses ear edema. In a rat HvG model, VX-509 (50 mg/kg, p.o.) results in dose-dependent inhibition of popletial lymph node (PLN) hyperplasia.
    Animal modelCollagen-induced arthritis (CIA) rat model
    Formulation & DosageDissolved in 10% vitamin E d-α-tocophenyl polyethylene glycol 1000 succinate and 1% hydroxypropyl methylcellulose acetyl succinate; 50 mg/kg; administrated orally
    References

    J Pharmacol Exp Ther. 2015 May;353(2):405-14; J Med Chem. 2015 Sep 24;58(18):7195-216.


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

    Decernotinib (VX-509)

    Effect of VX-509 on progression of established disease in rat CIA model. J Pharmacol Exp Ther. 2015 May;353(2):405-14.

    Decernotinib (VX-509)

    (A) Representative histopathology photomicrographs of a control (collagen + vehicle) rat ankle and VX-509 b.i.d. treatment groups, with approximate mean score for group showing synovium (S), cartilage (large arrow), and bone (small arrow). J Pharmacol Exp Ther.2015 May;353(2):405-14.

    Decernotinib (VX-509)

    Effect of VX-509 on the oxazolone-induced mouse DTH model. J Pharmacol Exp Ther. 2015 May;353(2):405-14.


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