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    LY3009120 (DP-4978)
    LY3009120 (DP-4978)

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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 #: V1015
    CAS #: 1454682-72-4Purity ≥98%

    Description: LY03009120 (DP4978; LY-3009120; LY-03009120; DP-4978)  is a novel and potent pan-Raf inhibitor with potential anticancer activity. It inhibits A-raf, B-Raf, and C-Raf with IC50s of 44 nM, 37 nM, and 42 nM, respectively. It has potent antitumor activity and showed activities against BRaf or Ras mutant tumor cells. It binds to ARaf, BRaf and CRaf isoforms with similar affinity in cells with activating mutations of BRaf or KRas. LY3009120 inhibits MEK phosphorylation and cell proliferation in vitro, and exhibits anti-tumor activity in multiple xenograft models carrying mutations in BRaf, NRas or KRas.

    References: [1] J Med Chem. 2015, 58(10), 4165-4179. [2] Chem Biol.011, 18(6), 699-710.

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    Molecular Weight (MW)424.51
    FormulaC23H29FN6O
    CAS No.1454682-72-4
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 3 mg/mL (7.1 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)0.5% CMC Na: 30 mg/mL
    SynonymsLY3009120; LY 3009120; DP4978; LY-3009120; DP 4978; DP-4978.


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    In Vitro

    In vitro activity: LY3009120 inhibits the cell growth of A375 and HCT116 cells with the IC50 of 9.2 and 220 μM, respectively. LY3009120 inhibits the tyrosine kinase KDR with the IC50 of 3.9 μM.


    Kinase Assay: Compounds are screened in A375 cell lysates using the ATP-based probe at 5 µM. IC50 values are reported in micromolar units. Cell pellets are resuspended in four volumes of lysis buffer [25 mM Tris pH 7.6, 150 mM NaCl, 1% CHAPS, 1% Tergitol NP-40 type, 1% v/v phosphatase inhibitor cocktail II], sonicated using a tip sonicator, and dounce homogenized. Lysates are cleared by centrifugation at 100,000 g for 30 min. The cleared lysates are filtered through a 0.22 μM syringe filter, and gel filtered into reaction buffer [20 mM Hepes pH 7.8, 150 mM NaCl, 0.1% triton X-100, 1% v/v phosphatase inhibitor cocktail II]. MnCl2 is then added to the lysate to a final concentration of 20 mM prior to inhibitor treatment and probe labeling. Final inhibitor concentrations used for IC50 determinations are 10, 1, 0.1, and 0.01 μM. ATP competition experiments are performed at 1,000, 100, 10, and 1 μM ATP. All inhibitor treatments are performed at room temperature.


    Cell Assay: Briefly, cells are grown in DMEM high glucose supplemented with 10% characterized fetal bovine serum and 1% penicillin/streptomycin/L -glutamine at 37℃, 5% CO2, and 95% humidity. Cells are allowed to expand until 70-95% confluency. A serial dilution of test compound is dispensed into a 384-well black clear bottom plate. 625 cells are added per well in 50 μL of complete growth medium. Plates are incubated for 67 h at 37℃, 5% CO2 , and 95% humidity. Then, 10 μL of a 440 μM solution of resazurin in PBS is added to each well of the plate and plates are incubated for an additional 5 h at 37℃, 5% CO2, and 95% humidity. Plates are read on a Synergy2 reader using an excitation of 540 nm and an emission of 600 nm. Data are analyzed using Prism software to calculate IC 50 values.

    In VivoIn rats bearing BRAF V600E ST019VR PDX tumors, LY3009120 (15 or 30 mg/kg, p.o.) shows a dose-dependent tumor growth inhibition. In nude rats bearing A375 xenograft, single dose oral treatment with LY3009120 (3 to 50 mg/kg, p.o.) shows a dose dependent inhibition of phospho-ERK, with a dose for 50% inhibition of phospho-ERK (EC50) of 4.36 mg/kg, with plasma concentration to achieve 50% inhibition of phospho-ERK (EC50) of 68.9 ng/mL or 165 nM.[
    Animal modelFemale NIH nude rats bearing BRAF V600E ST019VR PDX tumors
    Formulation & DosageFormulated in 20% cyclodextrin, 25 mM phosphate, pH2.0; 30 mg/kg; p.o.
    References

    [1] J Med Chem. 2015, 58(10), 4165-4179. [2] Chem Biol.011, 18(6), 699-710.


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

    LY3009120

    Treatment of two PDXs (M048R2.X2 and M063R.X2) that express the BRAFV600E/DK with 30 mg/kg dabrafenib or 15 mg/kg LY3009120 (n=8 tumors/group). Graphs represent tumor volume and dashed lines indicate start of treatment. Unpaired t test was performed at the last time point (*p < 0.05 and ***p < 0.005). Error bars indicate SD. Lower part depicts the immunoblotting for p-ERK and BRAF on M048R2.X2 and M063R.X2, treated with either dabrafenib or LY3009120 (each lane represents a tumor derived from an individual mouse). Cell Rep, 2016, 16(1):263-77

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