Sorafenib Tosylate

Catalog No.S1040 Synonyms: Bay 43-9006

Sorafenib Tosylate Chemical Structure

Molecular Weight(MW): 637.03

Sorafenib Tosylate is a multikinase inhibitor of Raf-1, B-Raf and VEGFR-2 with IC50 of 6 nM, 22 nM and 90 nM in cell-free assays, respectively.

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Cited by 63 Publications

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Biological Activity

Description Sorafenib Tosylate is a multikinase inhibitor of Raf-1, B-Raf and VEGFR-2 with IC50 of 6 nM, 22 nM and 90 nM in cell-free assays, respectively.
Targets
Raf-1 [1]
(Cell-free assay)
VEGFR2/Flk1 [1]
(Cell-free assay)
B-Raf [1]
(Cell-free assay)
B-Raf (V599E) [1]
(Cell-free assay)
PDGFRβ [1]
(Cell-free assay)
6 nM 15 nM 22 nM 38 nM 57 nM
In vitro

Sorafenib tosylate inhibits both wild-type and V599E mutant B-Raf activity with IC50 of 22 nM and 38 nM, respectively. Sorafenib tosylate 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 tosylate 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 tosylate 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 tosylate 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 tosylate inhibits the proliferation of HAoSMC and MDA-MB-231 cells with IC50 of 0.28 μM and 2.6 μM, respectively. [1] In addition to inhibition of the RAF/MEK/ERK signaling pathway, Sorafenib tosylate significantly inhibits the phosphorylation of eIF4E and down-regulates Mcl-1 levels in hepatocellular carcinoma (HCC) cells in a MEK/ERK-independent manner. Sorafenib tosylate 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. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MDA-MB-435 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXW0PEBp NH[zZnlIUTVyPUKg{txO MlX4NlI2PjB4Mke=
UACC257 NGLFeXdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2r3elQ5KGh? MUfHTVUxRTJizszN NIfsSJozOjV4ME[yOy=>
MCF7 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlyzOFghcA>? NEnsTVlIUTVyPUKuOUDPxE1? NFHXNo8zOjV4ME[yOy=>
EKVX MkLQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml\zOFghcA>? MYPHTVUxRTJwNTFOwG0> NUC1U5NwOjJ3NkC2Nlc>
HT-29 NID3V2VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoG4OFghcA>? MYHHTVUxRTJwNTFOwG0> NFjIbIczOjV4ME[yOy=>
SNB19 NWXVZ2l{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NF2ybHE1QCCq MYXHTVUxRTNwMjFOwG0> NX3iO5c{OjJ3NkC2Nlc>
OVCAR3 MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHzPWoc1QCCq NIThenpIUTVyPUOuNkDPxE1? NGTEbo4zOjV4ME[yOy=>
CAKI-1 NXrQNW46T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXTMXJhGPDhiaB?= MmKxS2k2OD1|LkKg{txO M3\HUVIzPTZyNkK3
SW620 MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoXxOFghcA>? MVfHTVUxRTNwMjFOwG0> NY\BOWR[OjJ3NkC2Nlc>
TK10 NGDSTVlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHvxWmQ1QCCq MljVS2k2OD13IN88US=> MkeyNlI2PjB4Mke=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
LC3-I / LC-3II / ATG5; 

PubMed: 23392173     


Sorafenib induces the conversion of LC3 in a dose-dependent manner. PLC5, Hep3B, SK-Hep1 and HepG2 were exposed to sorafenib at the indicated doses for 16 h and the expression levels of LC3-II were analyzed by western blot.

p-STAT3 / STAT3/ Mcl-1; 

PubMed: 23392173     


Effects of sorafenib on STAT3-related proteins in HCC cells. The cells were treated with sorafenib at the indicated dose for 16 h. 

β-catenin / Survivin / Mcl-1 / PTMA; 

PubMed: 26517516     


Co-inhibition of β-catenin and PTMA by sorafenib in HCC cells. Cell lines indicated on top were treated or not with 10 μM sorafenib for 24 hrs and processed for immuno-blotting. IC50 values (the concentration of sorafenib that inhibits 50% of cell growth) for each cell line are indicated below the panels.

pERK / ERK; 

PubMed: 22286758     


Western blot analysis of p-ERK (T202/Y204) and ERK at indicated time points in HCT116 cells treated with 20 μmol/L sorafenib.

p-PKM2(Y105) / PMK2 / Caspase-9 ; 

PubMed: 26959741     


Sorafenib downregulates the p-PKM2(Y105) at the indicated doses after treatment for 24 h.

RET(pY1016) / VEGFR2(pY1214) / MEK1(pT292) / ERK(pY204) ; 

PubMed: 22941289     


Sorafenib affected the phosphorylation of receptor tyrosine kinase RET and VEGFR2, as well as MEK/ERK kinases signaling cascades in three cell lines. Three cell lines were treated by sorafenib with two concentration gradients, 1 and 5 μmol/L/L, and then collected after 2, 4, and 8 h, cells without sorafenib treatment were as the controls (0 h). Total proteins were extracted and quantified to be used in Western blot assays. (A) Sorafenib inhibited RET and VEGFR2 phosphorylation dose-dependently while activated MEK and ERK phosphorylation in A549 cells. (B) Sorafenib also inhibited RET and VEGFR2 phosphorylation, and slightly activated MEK and ERK phosphorylation in HeLa cells. (C) Sorafenib activated the phosphorylation of RET, VEGFR2, and MEK, but inhibited ERK phosphorylation in HepG2 cells.

Cyclin D1; 

PubMed: 26039995     


Dose-escalation effects of sorafenib or SC-1 for 24 h on STAT3-related proteins in HSC-T6 and LX2 cells.

23392173 26517516 22286758 26959741 22941289 26039995
Immunofluorescence
p65; 

PubMed: 22286758     


HCT116 cells were treated with 20 μmol/L sorafenib or 10 ng/mL TNF-α for 3 hours then fixed. Immunofluorescence was carried out as described in the Materials and Methods for p65 (green) and DAPI (blue). Representative pictures (400×) are shown

cytochrome c; 

PubMed: 22278289     


Immunoflourescent staining and quantification of mitochondrial membrane potential (appearing in red, mitotracker) and cytochrome c (appearing in green, FITC) in 22Rv1 and PC3 treated with 20 μM sorafenib for 24 h

22286758 22278289
Growth inhibition assay
Cell viability; 

PubMed: 26039995     


Dose-escalation and time-dependent effects of sorafenib for 24 or 48 h on cell viability in HSC-T6, LX2, and mouse primary HSCs. Circles, mean; bars, SE (n = 3). 

26039995
ELISA
TGF-beta / CD206; 

PubMed: 26158762     


In Macrophage, TGF-β secretion and CD206 were confirmed by ELISA.

Caspase-9 / Caspase-3; 

PubMed: 30923462     


Caspase-9 and caspase-3 activities were measured via ELISA assay. FCCP, an activator of mitophagy, was added into the medium of sorafenib-treated cells to activate mitophagy. Adenovirus-loaded LATS2 (Ad-LATS2) was transfected into HepG2 cells in the presence of sorafenib. *p < 0.05 vs. control group; #p < 0.05 vs. Sorafenib + Ad-cont group; #p < 0.05 vs. Sorafenib + Ad-LATS2 group

26158762 30923462
In vivo Oral administration of Sorafenib tosylate (~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 tosylatetreatment 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. [1] Sorafenib tosylate 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. [2]

Protocol

Kinase Assay:[1]
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Biochemical assays:

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 Research:[1]
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  • Cell lines: MDA-MB-231, and HAoSMC
  • Concentrations: Dissolved in DMSO, final concentrations ~10 μM
  • Incubation Time: 72 hours
  • Method: Cells 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.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female NCr-nu/nu mice implanted s.c. with MDA-MB-231, Colo-205, HT-29, H460, or A549 cells
  • Formulation: Dissolved in Cremophor EL/ethanol (50:50) as 4-fold (4 × stock solution, and diluted to 1 × with w
  • Dosages: ~60 mg/kg
  • Administration: Orally once daily
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 127 mg/mL (199.36 mM)
Water 0.01 mg/mL (0.01 mM)
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% Cremophor EL, 2% N,N-dimethylacetamide
For best results, use promptly after mixing.
30 mg/mL (suspension)

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 637.03
Formula

C21H16ClF3N4O3.C7H8O3S

CAS No. 475207-59-1
Storage powder
in solvent
Synonyms Bay 43-9006

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID