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  3. LY3009120

LY3009120 (Synonyms: DP-4978)

Cat. No.: HY-12558 Purity: 98.31%
Handling Instructions

LY3009120 is a pan RAF inhibitor which inhibits BRAFV600E, BRAFWT and CRAFWT with IC50s of 5.8, 9.1 and 15 nM, respectively.

For research use only. We do not sell to patients.

LY3009120 Chemical Structure

LY3009120 Chemical Structure

CAS No. : 1454682-72-4

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10 mM * 1 mL in DMSO USD 132 In-stock
Estimated Time of Arrival: December 31
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10 mg USD 180 In-stock
Estimated Time of Arrival: December 31
50 mg USD 540 In-stock
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100 mg USD 816 In-stock
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Top Publications Citing Use of Products

    LY3009120 purchased from MCE. Usage Cited in: Oncogene. 2018 Jun 21.

    BRAF mutants with in-frame β3-αC loop deletions have approximate sensitivities to RAF dimer inhibitor, LY3009120.

    LY3009120 purchased from MCE. Usage Cited in: Clin Sci (Lond). 2019 Apr 3. pii: CS20181081.

    LY3009120 decreases phosphorylation of RIPK1, RIPK3 and MLKL in T/S/Z treated HT-29 cells. HT-29 cells are pretreated with DMSO or LY3009120 for 1 hour, then treated with T/S/Z for 0, 2, 4 and 6 hours, respectively.

    LY3009120 purchased from MCE. Usage Cited in: Clin Sci (Lond). 2019 Apr 3. pii: CS20181081.

    Colonic proteins on day 7 are tested by immunoblotting to detect p-MLKL, MLKL and cleaved caspase-3 with corresponding antibodies. GAPDH is used as an internal control. Three individual mice from each group are shown.

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    • Biological Activity

    • Protocol

    • Technical Information

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    • References

    Description

    LY3009120 is a pan RAF inhibitor which inhibits BRAFV600E, BRAFWT and CRAFWT with IC50s of 5.8, 9.1 and 15 nM, respectively.

    IC50 & Target[1]

    BRafV600E

    5.8 nM (IC50)

    Braf

    9.1 nM (IC50)

    CRAF

    15 nM (IC50)

    In Vitro

    In the whole-cell based KiNativ assay, LY3009120 shows affinity to each RAF isoform with the IC50 of 44, 31-47 and 42 nM for ARAF, BRAF and CRAF respectively. LY3009120 exhibits anti-proliferative effects on cell lines harboring BRAFV600E, KRASG13 and KRASG12 mutations. LY3009120 (1 μM) inhibits the phosphorylation of both MEK1/2 and ERK1/2 in cell lines with high basal levels of pMEK1/2 and pERK1/2 (RKO and HCT 116)[1]. LY3009120 shows inhibitory effect on tumor cells such as BxPC-3, NCI-H2405 and OV-90 cell lines. LY3009120 (0.01 μM) demonstrates potent and dose-dependent inhibition of phospho-MEK and ERK in all three cell lines. LY3009120 demonstrates a concentration-dependent cell growth inhibition with IC50 values of 0.04, 0.087, and 0.007 μM against H2405, BxPC-3, and OV-90 cells, respectively[2]. LY3009120 inhibits BRAFWT, CRAFWT, BRAFV600E, and BRAFV600E+G468A with the IC50 values of 9.1, 15, 5.8, and 17 nM, respectively. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK. LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers[3]. LY3009120 gives only very minor activation at very low doses, with near complete inhibition of phospho-ERK at concentrations above 100 nM[4].

    In Vivo

    LY3009120 (20 mg/kg bid) displays significant activity in in vivo BRAFmut and KRASmut CRC xenograft models. In Colo 205 xenografts (BRAFmut), LY3009120 results in statistically significant tumor regression, while treatment of HCT 116 xenografts (KRASmut) results in statistically significant inhibition of tumor growth. LY3009120 treatment reduces pMEK1/2 in all HT-29 xenografts and reduces pERK1/2 in the majority of HT-29 xenografts[1]. LY3009120 (15 or 30 mg/kg) achieves almost complete tumor growth regression, and inhibits downstream phospho-MEK and ERK by approximately 70% and 60%, respectively, in the H2405 model[2].

    Clinical Trial
    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Solvent & Solubility
    In Vitro: 

    DMSO : ≥ 38 mg/mL (89.51 mM)

    *"≥" means soluble, but saturation unknown.

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 2.3557 mL 11.7783 mL 23.5566 mL
    5 mM 0.4711 mL 2.3557 mL 4.7113 mL
    10 mM 0.2356 mL 1.1778 mL 2.3557 mL
    *Please refer to the solubility information to select the appropriate solvent.
    References
    Kinase Assay
    [3]

    In the BRAF WT enzymatic assay, the reaction mixture contains 1.2 nM BRAF, 30 nM MEK1, 1000 µM ATP, 3.5 units (per 100 µL) of PK, 5 units (per 100 µL) of LDH, 1 mM PEP, and 280 µM of NADH. In the CRAF assay, the reaction mixture contains 0.6 nM CRAF, 26 nM MEK1, 2000 µM ATP, and the same amount of PK, LDH, PEP and NADH. In the BRAFV600E assay, the reaction mixture contains 1.6 µM BRAFV600E, 26 nM MEK1, 200 µM ATP and the same amount of PK, LDH, PEP and NADH as above. In the BRAFV600E+G468A assay, the reaction mixture contains 3.5 nM BRAF, 30 nM MEK1, 200 µM ATP and the same amount of PK, LDH, PEP and NADH as above. All assays are started by mixing the above mixture with test compound and monitored at A340 continuously for approximately 5 hr. Reaction data at the 3 to 4 hour time frame are collected to calculate IC50.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [4]

    Briefly, cells are grown in McCoy’s 5A supplemented with 10% characterized fetal bovine serum and 1% penicillin/streptomycin/l-glutamine at 37°C, 5% CO2, and 95% humidity. Cells are allowed to expand until 75-90% confluency at which point they are subcultured or harvested for assay use. A serial dilution of test compound is dispensed into a 384-well black clear bottom plate in triplicate. Six-hundred-twenty-five cells are added per well in 50 μL of complete growth medium in the 384-well plate. Plates are incubated for 67 h at 37°C, 5% CO2, and 95% humidity. At the end of the incubation period, 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°C, 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 softwareto calculate IC50 values.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [2]

    Briefly, 5×106 to 10×106 tumor cells in a 1:1 Matrigel mix (0.2 mL total volume) are injected subcutaneously into the right hind flank of female NIH nude rats. After tumors reach a desired size of approximately 300 mm3, animals are randomized into groups of 8 for efficacy studies. Drugs (LY3009120 or vemurafenib) are administered orally (gavage) in 0.6-mL volume of vehicle with the dose schedules. Tumor growth and body weight are monitored over time to evaluate efficacy and signs of toxicity.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    424.51

    Formula

    C₂₃H₂₉FN₆O

    CAS No.

    1454682-72-4

    SMILES

    O=C(NC1=CC(C2=CC3=CN=C(NC)N=C3N=C2C)=C(C)C=C1F)NCCC(C)(C)C

    Shipping

    Room temperature in continental US; may vary elsewhere

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    Cat. No.: HY-12558