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    WH-4-023
    WH-4-023

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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 #: V0670
    CAS #: 837422-57-8Purity ≥98%

    Description: WH-4-023 (also called KIN112; WH-4023; KIN-001-112) is a novel, potent, selective and orally bioactive inhibitor of Src family kinase (dual Lck/Src inhibitor) with potential anti-inflammatory and anticancer activity. It inhibits dual Lck/Src kinases with IC50s of 2 nM and 6 nM in cell-free assays, respectively. WH-4-023 increased LPS-stimulated IL-10 production and greatly suppressed proinflammatory cytokine secretion.

    References: J Med Chem. 2006 Aug 10;49(16):4981-91.

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    Molecular Weight (MW)568.67
    FormulaC32H36N6O4
    CAS No.837422-57-8
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 12 mg/mL (21.1 mM)   
    Water: <1 mg/mL
    Ethanol: 6 mg/mL (10.55 mM) 
    Other info

    Chemical Name: 2,6-dimethylphenyl (2,4-dimethoxyphenyl)(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)carbamate

    InChi Key: NBTNHSGBRGTFJS-UHFFFAOYSA-N

    InChi Code: InChI=1S/C32H36N6O4/c1-22-7-6-8-23(2)30(22)42-32(39)38(27-14-13-26(40-4)21-28(27)41-5)29-15-16-33-31(35-29)34-24-9-11-25(12-10-24)37-19-17-36(3)18-20-37/h6-16,21H,17-20H2,1-5H3,(H,33,34,35)

    SMILES Code: O=C(OC1=C(C)C=CC=C1C)N(C2=CC=C(OC)C=C2OC)C3=NC(NC4=CC=C(N5CCN(C)CC5)C=C4)=NC=C3

    SynonymsKIN001-112, KIN112; WH-4023; KIN-001-112, KIN-112; KIN 001-112, KIN 112; WH-4-023; WH4-023; WH 4-023; WH 4023; WH4023;


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    In Vitro

    In vitro activity: WH-4-023 inhibited a number of protein tyrosine kinases that possess a Thr residue at the gatekeeper site, such as FGF and Ephrin receptors, Src family members (Src, Lck, and Yes) and BTK. WH-4-023 also inhibited the SIKs and did not inhibit any other member of the AMPK-related kinase subfamily, which all possess a large hydrophobic residue (Met or Leu) at the gatekeeper site. WH-4-023 inhibited SIK 1, 2 and 3 with IC50 values of 10, 22 and 60 nM, respectively. Also, WH-4-023 increased LPS-stimulated IL-10 production and greatly suppressed proinflammatory cytokine secretion.


    Kinase Assay: The Lck HTRF kinase assay involves ATP-dependent phosphorylation of a biotinylated substrate peptide of gastrin in the presence or absence of inhibitor compound. The final concentration of gastrin is 1.2 μM. The final concentration of ATP is 0.5 μM (Km app =0.6±0.1 μM), and the final concentration of Lck (a GST-kinase domain fusion (AA 225−509)) is 250 pM. Buffer conditions are as follows: 50 mM HEPES pH=7.5, 50 mM NaCl, 20 mM MgCl2, 5 mM MnCl2, 2 mM DTT, 0.05% BSA. The assay is quenched and stopped with 160 μL of detection reagent. Detection reagents are as follows: Buffer made of 50 mM Tris, pH=7.5, 100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Prior to reading, Streptavidin allophycocyanin (SA-APC) is added at a final concentration in the assay of 0.0004 mg/mL, along with europilated anti-phosphotyrosine Ab (Eu-anti-PY) at a final conc of 0.025 nM. The assay plate is read in a Discovery fluorescence plate reader with excitation at 320 nm and emission at 615 and 655 nm


    Cell Assay: The purpose of this assay is to test the potency of T cell receptor (TCR; CD3) and CD28 signaling pathway inhibitors in human T cells. T cells are purified from human peripheral blood lymphocytes (hPBL) and preincubated with or without compound prior to stimulation with a combination of an anti-CD3 and an anti-CD28 antibody in 96-well tissue culture plates (1×105 T cells/well). Cells are cultured for ~20 h at 37°C in 5% CO2 and then secreted IL-2 in the supernatants is quantified by cytokine ELISA. The cells remaining in the wells are then pulsed with 3H-thymidine overnight to assess the T cell proliferative response. Cells are harvested onto glass fiber filters and 3H-thymidine incorporation into DNA is analyzed by liquid scintillation counter. For comparison purposes, phorbol myristic acid (PMA) and calcium ionophore are used in combination to induce IL-2 secretion from purified T cells. Potential inhibitor compounds are tested for inhibition of this response as described above for anti-CD3 and -CD28 antibodies. Human whole-blood anti-CD3/CD28-induced IL-2 secretion assays are run in a similar fashion as described above using whole blood from normal volunteers diluted 50% in tissue culture medium prior to stimulation

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    References

    J Med Chem. 2006 Aug 10;49(16):4981-91


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

    WH-4-023

    X-ray crystal structure reported in this article. J Med Chem. 2006 Aug 10;49(16):4981-91.

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