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    Sorafenib (Bay 43-9006)
    Sorafenib (Bay 43-9006)

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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 #: V1010
    CAS #: 284461-73-0 Purity ≥98%

    Description: Sorafenib (BAY549085; BAY-549085; BAY439006; BAY-439006; Nexavar; SFN), an approved anticancer drug, is a potent and orally bioavailable multikinase inhibitor with potential anticancer activity. It inhibits multiple kinases including Raf-1, B-Raf and VEGFR-2 with IC50 of 6 nM, 22 nM and 90 nM in enzymatic assays, respectively. Sorafenib was approved by FDA in 2005 for the treatment of advanced renal cancer. 

    References: Cancer Res. 2004 Oct 1;64(19):7099-109; Cancer Res. 2006 Dec 15;66(24):11851-8.

    Related CAS#: 475207-59-1 (tosylate)

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    Molecular Weight (MW)464.82
    FormulaC21H16ClF3N4O3
    CAS No.284461-73-0 (free base);
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 63 mg/mL (135.5 mM)          
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Other infoChemical Name: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide
    InChi Key: MLDQJTXFUGDVEO-UHFFFAOYSA-N
    InChi Code: InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
    SMILES Code: O=C(C1=NC=CC(OC2=CC=C(C=C2)NC(NC3=CC=C(C(C(F)(F)F)=C3)Cl)=O)=C1)NC
    SynonymsBAY 43-9006; BAY-439-006; BAY439006; BAY-439006; BAY 439006; BAY 549085; trade name: Nexavar; SFN.



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    In Vitro

    In vitro activity: Sorafenib inhibits both wild-type and V599E mutant B-Raf activity with IC50 of 22 nM and 38 nM, respectively. Sorafenib also potently inhibits mVEGFR2 (Flk-1), mVEGFR3, mPDGFRβ, Flt3, and c-Kit with IC50 of 15 nM, 20 nM, 57 nM, 58 nM, and 68 nM, respectively. Sorafenib weakly inhibits FGFR-1 with IC50 of 580 nM. Sorafenib tosylate is not active against ERK-1, MEK-1, EGFR, HER-2, IGFR-1, c-Met, PKB, PKA, cdk1/cyclinB, PKCα, PKCγ, and pim-1. Sorafenib markedly inhibits VEGFR2 phosphorylation in NIH 3T3 cells with IC50 of 30 nM, and Flt-3 phosphorylation in HEK-293 cells with IC50 of 20 nM. Sorafenib potently blocks MEK 1/2 and ERK 1/2 phosphorylation in most cell lines but not in A549 or H460 cells, while having no effect on inhibition of the PKB pathway. Sorafenib inhibits the proliferation of HAoSMC and MDA-MB-231 cells with IC50 of 0.28 μM and 2.6 μM, respectively. In addition to inhibition of the RAF/MEK/ERK signaling pathway, Sorafenib significantly inhibits the phosphorylation of eIF4E and down-regulates Mcl-1 levels in hepatocellular carcinoma (HCC) cells in a MEK/ERK-independent manner. Sorafenib inhibits the proliferation of PLC/PRF/5 and HepG2 cells with IC50 of 6.3 μM and 4.5 μM, respectively, and leads to the significant induction of apoptosis.


    Kinase Assay: Recombinant baculoviruses expressing Raf-1 (residues 305–648) and B-Raf (residues 409–765) are purified as fusion proteins. Full-length human MEK-1 is generated by PCR and purified as a fusion protein from Escherichia coli lysates. Sorafenib tosylate is added to a mixture of Raf-1 (80 ng), or B-Raf (80 ng) with MEK-1 (1 μg) in assay buffer [20 mM Tris (pH 8.2), 100 mM NaCl, 5 mM MgCl2, and 0.15% β-mercaptoethanol] at a final concentration of 1% DMSO. The Raf kinase assay (final volume of 50 μL) is initiated by adding 25 μL of 10 μM γ[33P]ATP (400 Ci/mol) and incubated at 32 °C for 25 minutes. Phosphorylated MEK-1 is harvested by filtration onto a phosphocellulose mat, and 1% phosphoric acid is used to wash away unbound radioactivity. After drying by microwave heating, a β-plate counter is used to quantify filter-bound radioactivity. Human VEGFR2 (KDR) kinase domain is expressed and purified from Sf9 lysates. Time-resolved fluorescence energy transfer assays for VEGFR2 are performed in 96-well opaque plates in the time-resolved fluorescence energy transfer format. Final reaction conditions are as follows: 1 to 10 μM ATP, 25 nM poly GT-biotin, 2 nM Europium-labeled phospho (p)-Tyr antibody (PY20), 10 nM APC, 1 to 7 nM cytoplasmic kinase domain in final concentrations of 1% DMSO, 50 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1 mM EDTA, 0.015% Brij-35, 0.1 mg/mL BSA, and 0.1% β-mercaptoethanol. Reaction volumes are 100 μL and are initiated by addition of enzyme. Plates are read at both 615 and 665 nM on a Perkin-Elmer VictorV Multilabel counter at ~1.5 to 2.0 hours after reaction initiation. Signal is calculated as a ratio: (665 nm/615 nM) × 10,000 for each well. For IC50 generation, Sorafenib tosylate is added before the enzyme initiation. A 50-fold stock plate is made with Sorafenib tosylate serially diluted 1:3 in a 50% DMSO/50% distilled water solution. Final Sorafenib tosylate concentrations range from 10 μM to 4.56 nM in 1% DMSO. 


    Cell Assay: Cells (MDA-MB-231, and HAoSMC) are exposed to increasing concentrations of Sorafenib tosylate for 72 hours. Cell number is quantitated using the Cell TiterGlo ATP Luminescent assay kit. This assay measures the number of viable cells per well by measurement of luminescent signal based on amount of cellular ATP.

    In VivoOral administration of Sorafenib (~60 mg/kg) demonstrates broad spectrum, dose-dependent anti-tumor activity against a variety of human tumor xenograft models including MDA-MB-231, Colo-205, HT-29, DLD-1, NCI-H460, and A549, with no evidence of toxicity. In association with the anti-tumor efficacy, Sorafenib treatment potently inhibits MEK 1/2 phosphorylation and pERK 1/2 levels in HT-29 and MDA-MB-231 xenografts but not in Colo-205 xenografts, and significantly suppresses tumor microvessel area (MVA) and microvessel density (MVD) in MDA MB-231, HT-29 and Colo-205 tumor xenografts. Sorafenib treatment produces dose-dependent growth inhibition of PLC/PRF/5 tumor xenografts in SCID mice with TGIs of 49% and 78% at 10 mg/kg and 30 mg/kg, respectively, consistent with the inhibition of ERK and eIF4E phosphorylation, reduction of the microvessel area, and induction of tumor cell apoptosis. Sorafenib sensitizes bax-/- cells to TRAIL in a dose-dependent manner, through a mechanism involving down-regulating NF-κB mediated Mcl-1 and cIAP2 expression. Combining Sorafenib (30-60 mg/kg) with TRAIL (5 mg/kg) show dramatic efficacy in TRAIL-resistant HCT116 bax-/- and HT29 tumor xenografts.
    Animal modelFemale NCr-nu/nu mice implanted s.c. with MDA-MB-231, Colo-205, HT-29, H460, or A549 cells
    Formulation & DosageDissolved in Cremophor EL/ethanol (50:50) as 4-fold (4 × stock solution, and diluted to 1 × with water; 60 mg/kg; p.o.
    References

    Cancer Res. 2004 Oct 1;64(19):7099-109; Cancer Res. 2006 Dec 15;66(24):11851-8.


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

    Sorafenib free base

    The number of nuclei breaking the internal limiting membrane (ILM). A: Controlled group; B: ROP group; C: Vehicle-treated ROP group; D: Low doses sorafenib-treated ROP group; E: Middle doses sorafenib-treated ROP group; F: High dose sorafenib-treated ROP group.

    Sorafenib free base
    Sorafenib free base


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