Sorafenib Tosylate

Catalog No.S1040

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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Sorafenib Tosylate Chemical Structure

Sorafenib Tosylate Chemical Structure
Molecular Weight: 637.03

Validation & Quality Control

Cited by 40 publications:

4 customer reviews :

Quality Control & MSDS

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

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)

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IC50 6 nM 15 nM 22 nM 38 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 LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
MDA-MB-435MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MUS0PEBpMU\HTVUxRTJizszNNIDVe|UzOjV4ME[yOy=>
UACC257M4XEVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MWK0PEBpM{TjTGdKPTB;MjFOwG0>M3iwS|IzPTZyNkK3
MCF7M{LpeGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MkHuOFghcA>?M4\SSGdKPTB;Mj61JO69VQ>?MkLDNlI2PjB4Mke=
EKVXM1fMNWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7MoDEOFghcA>?NEDJOWtIUTVyPUKuOUDPxE1?Ml[zNlI2PjB4Mke=
HT-29Mkn0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NETXTmM1QCCqMV\HTVUxRTJwNTFOwG0>M1jjZVIzPTZyNkK3
SNB19M{LFXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7NFPlZZA1QCCqNV[4W2ZST0l3ME2zMlIh|ryPMoLGNlI2PjB4Mke=
OVCAR3MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MlnjOFghcA>?MVLHTVUxRTNwMjFOwG0>M2\tZVIzPTZyNkK3
CAKI-1Mly4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NFTG[XQ1QCCqMW\HTVUxRTNwMjFOwG0>NFzuN2IzOjV4ME[yOy=>
SW620MkXjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl?NH;6R4k1QCCqM2jneWdKPTB;Mz6yJO69VQ>?MVuyNlU3ODZ{Nx?=
TK10MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MlLsOFghcA>?NGjUdXpIUTVyPUWg{txONID2fXYzOjV4ME[yOy=>

... Click to View More Cell Line Experimental Data

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]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

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 Assay: [1]

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.

Animal Study: [1]

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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Wilhelm SM, et al. Cancer Res, 2004, 64(19), 7099-7109.

[2] Liu L, et al. Cancer Res, 2006, 66(24), 11851-11858.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02728050 Not yet recruiting Acute Biphenotypic Leukemia|Acute Myeloid Leukemia|de Novo Myelodysplastic Syndrome|Myeloproliferative Neoplasm University of Washington|National Cancer Institute (NCI) May 2016 Phase 1|Phase 2
NCT02779283 Recruiting Untreated Adult Acute Myeloid Leukemia OHSU Knight Cancer Institute|National Cancer Institute (NCI) December 2015 Phase 1
NCT02143401 Recruiting Recurrent Hepatocellular Carcinoma|Solid Neoplasm|Stage IV Hepatocellular Carcinoma National Cancer Institute (NCI) November 2014 Phase 1
NCT02035527 Active, not recruiting Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma|Recurrent Metastatic Squamous Neck Cancer With Occult Primary|Recurrent  ...more Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma|Recurrent Metastatic Squamous Neck Cancer With Occult Primary|Recurrent Salivary Gland Cancer|Recurrent Squamous Cell Carcinoma of the Hypopharynx|Recurrent Squamous Cell Carcinoma of the Larynx|Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity|Recurrent Squamous Cell Carcinoma of the Nasopharynx|Recurrent Squamous Cell Carcinoma of the Oropharynx|Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Recurrent Verrucous Carcinoma of the Larynx|Recurrent Verrucous Carcinoma of the Oral Cavity|Salivary Gland Squamous Cell Carcinoma|Stage IV Squamous Cell Carcinoma of the Hypopharynx|Stage IV Squamous Cell Carcinoma of the Nasopharynx|Stage IVA Salivary Gland Cancer|Stage IVA Squamous Cell Carcinoma of the Larynx|Stage IVA Oral Cavity Squamous Cell Carcinoma|Stage IVA Squamous Cell Carcinoma of the Oropharynx|Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Stage IVA Verrucous Carcinoma of the Larynx|Stage IVA Verrucous Carcinoma of the Oral Cavity|Stage IVB Salivary Gland Cancer|Stage IVB Squamous Cell Carcinoma of the Larynx|Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity|Stage IVB Squamous Cell Carcinoma of the Oropharynx|Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Stage IVB Verrucous Carcinoma of the Larynx|Stage IVB Verrucous Carcinoma of the Oral Cavity|Stage IVC Salivary Gland Cancer|Stage IVC Squamous Cell Carcinoma of the Larynx|Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity|Stage IVC Squamous Cell Carcinoma of the Oropharynx|Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity|Stage IVC Verrucous Carcinoma of the Larynx|Stage IVC Verrucous Carcinoma of the Oral Cavity|Tongue Cancer|Untreated Metastatic Squamous Neck Cancer With Occult Primary Ohio State University Comprehensive Cancer Center|Nationa  ...more Ohio State University Comprehensive Cancer Center|National Comprehensive Cancer Network April 2014 Phase 1|Phase 2
NCT02066181 Suspended Desmoid-Type Fibromatosis National Cancer Institute (NCI) March 2014 Phase 3

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Chemical Information

Download Sorafenib Tosylate SDF
Molecular Weight (MW) 637.03
Formula

C21H16ClF3N4O3.C7H8O3S

CAS No. 475207-59-1
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms Bay 43-9006
Solubility (25°C) * In vitro DMSO 127 mg/mL (199.36 mM)
Water 0.01 mg/mL (0.01 mM)
Ethanol <1 mg/mL
In vivo 2% Cremophor EL, 2% N,N-dimethylacetamide 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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 Name 2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-, 4-methylbenzenesulfonate (1:1)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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